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MONDO:0008437 hereditary spastic paraplegia 3A

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Inheritance

2

Autosomal dominant HP:0000006

ATL1-HSP is almost exclusively inherited in an autosomal dominant manner, and more than 95% of diagnosed individuals have an affected parent. Penetrance is incomplete: clinically unaffected carriers are recorded in several series, including one large French cohort in which five carriers were affected but asymptomatic and two had no clinical signs. De novo variants occur and are enriched among the severe complex presentations.

autosomal dominant inheritance

Show evidence (5 references)

PMID:20862796 SUPPORT Human Clinical

"ATL1-HSP is almost exclusively inherited in an autosomal dominant manner. More than 95% of individuals diagnosed with SPG3A have an affected parent"

GeneReviews statement of the mode of inheritance and the proportion of inherited cases.

PMID:20862796 SUPPORT Human Clinical

"Each child of an individual with ATL1-HSP has a 50% chance of inheriting the pathogenic variant."

The transmission risk that follows from dominant inheritance, cited separately as a quantitative counselling claim.

PMID:15596607 SUPPORT Human Clinical

"In addition, several gene carriers were clinically affected but still asymptomatic (n = 5) or had no clinical signs (n = 2), indicating incomplete penetrance."

Documents incomplete penetrance in the French SPG3A families.

+ 2 more references

Autosomal recessive HP:0000007

A rare recessive form is supported by a few consanguineous families in which affected members are homozygous for an ATL1 missense, splice-donor or frameshift variant while heterozygous relatives are asymptomatic. GeneReviews records two such families as the exception to dominant inheritance; further homozygous families have been reported since. This mode is curated as rare and emerging, not as coequal with dominant disease.

autosomal recessive inheritance

Show evidence (4 references)

PMID:20862796 SUPPORT Human Clinical

"Note: The exceptions are two families with biallelic ATL1 pathogenic variants."

GeneReviews records the biallelic exception to the dominant pattern.

PMID:24473461 SUPPORT Human Clinical

"Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced..."

The first consanguineous family with homozygous ATL1 disease and asymptomatic heterozygous carriers.

PMID:37927245 SUPPORT Human Clinical

"Exome sequencing reveals homozygosity for a novel likely pathogenic ATL1 splice donor variant (c.522+1G>T) in an affected 5-year-old infant whereas the parents, heterozygous carriers, are asymptomatic."

A third consanguineous family, here with a homozygous splice-donor variant.

+ 1 more reference

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Subtypes

3

Pure (uncomplicated) SPG3A

The majority presentation: early-childhood-onset, slowly progressive, bilateral lower-limb spasticity and weakness without additional neurological features, and with dorsal-column sensory loss and bladder symptoms in only a minority.

Show evidence (2 references)

PMID:20862796 SUPPORT Human Clinical

"Most persons with early-onset ATL1-HSP have a "pure" ("uncomplicated") HSP"

GeneReviews identifies the pure form as the usual presentation.

PMID:15596607 SUPPORT Human Clinical

"The main clinical characteristic of these SPG3A patients was pure spasticity with very young onset of symptoms (mean age, 4.6 +/- 3.9 years) and slow progression."

The French 34-patient series characterises the pure, early-onset, slowly progressive phenotype.

Complicated SPG3A with axonal neuropathy (Silver syndrome phenotype)

About 17% of SPG3A mutation carriers in one 182-family screen had an axonal sensorimotor neuropathy with lower motor neuron involvement and distal amyotrophy, the Silver syndrome phenotype. No genotype predicts the neuropathy, and subclinical axonal polyneuropathy is found on electrophysiology in further cases.

Show evidence (2 references)

PMID:17502470 SUPPORT Human Clinical

"Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy."

Quantifies the neuropathy-complicated fraction and characterises it as axonal sensorimotor.

PMID:20862796 SUPPORT Human Clinical

"complicated HSP with axonal motor neuropathy and/or distal amyotrophy with lower motor neuron involvement (Silver syndrome phenotype) has been observed."

GeneReviews names the complicated Silver-syndrome-like presentation.

Severe very-early-onset complex SPG3A (de novo mutational cluster or biallelic)

A distinct phenotype, delineated across 537 published and novel cases, in which variants in a three-dimensional mutational cluster of atlastin-1 (enriched for de novo variants, and also seen with some inherited ones) produce neurodevelopmental abnormalities, upper-limb spasticity, bulbar symptoms, peripheral neuropathy and brain-imaging abnormalities. The most severe cases begin in the first months of life with axial hypotonia followed by spastic quadriplegia, dystonia, seizures and intellectual disability, and are frequently first diagnosed as cerebral palsy. Biallelic ATL1 variants produce a similar severe early-onset picture.

Show evidence (5 references)

PMID:35925862 SUPPORT Human Clinical

"Establishing genotype-phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with..."

Defines the complex phenotype and ties it to a structural mutational cluster in atlastin-1.

PMID:35925862 SUPPORT Human Clinical

"we demonstrate that this distinct phenotypic signature is also prevalent in a subgroup of patients with inherited ATL1 variants and is largely explained by variant localization within a three-dimensional mutational cluster."

The cluster, not de novo status itself, explains the phenotype, so inherited cluster variants belong to this subtype too.

PMID:39003427 SUPPORT Human Clinical

"Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability). For 2 of the 3 patients, these phenotypes led to the initial diagnosis of..."

The three most severe reported cases, with the cerebral palsy misdiagnosis that characterises this subtype.

+ 2 more references

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Mechanistic Hypotheses

3

Impaired atlastin-1 ER tubule fusion disrupts the axonal ER network

er_fusion_deficit CANONICAL

Evidence balance 2 support

Disease variants reduce GTP hydrolysis-coupled homotypic fusion of ER tubules, the tubular ER fails to form three-way junctions and to extend along the axon, and the long corticospinal axon loses the membrane, lipid and calcium-handling functions of a continuous ER. This is the model that the atlastin structural and reconstitution work, the atlastin-null fly and worm, the triple-knockout cell lines and the K80A knock-in mouse all support.

Pathograph links

ATL1 Variant Impairing the Atlastin-1 GTPase Cycle -> Impaired Homotypic ER Tubule Fusion DIRECT The GTPase cycle is what drives fusion, so an allele that blocks GTP hydrolysis or crossover dimerisation cannot support the fusion reaction.

Impaired Homotypic ER Tubule Fusion -> Disrupted Tubular ER Network in Neurons DIRECT Interconnection of ER tubules into a polygonal network depends on atlastin-mediated fusion, so fusion failure leaves long unbranched tubules with few three-way junctions.

Disrupted Tubular ER Network in Neurons -> Impaired Axonal ER Distribution, Organelle Transport and Axon Growth DIRECT A fragmented ER cannot be carried into and along the growing axon, and its coupling to microtubules and mitochondria is lost, which is why microtubule-binding agents rescue the axon-growth defect of SPG3A neurons.

Show evidence (2 references)

PMID:21368113 SUPPORT In Vitro

"Finally, our results show that mutations in ATL1 causing hereditary spastic paraplegia compromise homotypic ER fusion."

Structural and fusion-assay demonstration that disease variants compromise the fusion reaction.

PMID:25761634 SUPPORT In Vitro

"Taken together, these findings indicate that a deficit in the membrane fusion activity of atlastin1 may be a key contributor, but is not required, for HSP causation."

Cited on the canonical hypothesis because it both supports a fusion deficit as a key contributor and bounds the claim: fusion loss is not required for disease.

Fusion-independent functions of atlastin-1 (BMP receptor trafficking, calcium entry) contribute to axonopathy

fusion_independent_variant_effects ALTERNATIVE

Evidence balance 3 support

At least two disease variants, including the most frequently identified one, retain wild-type ER network formation, GTPase, dimerisation and fusion activity, so a fusion deficit cannot be the whole explanation. Candidate fusion-independent mechanisms are dominant-negative disruption of BMPRII trafficking with dysregulated BMP signalling, which in zebrafish controls motor axon architecture, and reduced store-operated calcium entry.

Pathograph links

ATL1 Variant Impairing the Atlastin-1 GTPase Cycle -> Dysregulated BMP Signalling from Impaired BMPRII Trafficking DIRECT Mutant atlastin-1 binds BMPRII and, in a dominant-negative manner, blocks its trafficking to the cell surface; this does not require loss of fusion activity.

Dysregulated BMP Signalling from Impaired BMPRII Trafficking -> Impaired Axonal ER Distribution, Organelle Transport and Axon Growth INDIRECT UNKNOWN INTERMEDIATES BMP signalling tunes motor axon architecture; in atlastin-depleted zebrafish, inhibiting BMP signalling is sufficient to rescue the motor axon defects, so the BMP arm feeds into the axonal phenotype.

Show evidence (3 references)

PMID:25761634 SUPPORT In Vitro

"Surprisingly however, at least two disease variants, one of which represents that most frequently identified in SPG3A HSP patients, displayed wild-type levels of activity in all assays."

The observation that motivates a fusion-independent mechanism.

PMID:23079343 SUPPORT In Vitro

"Our results suggest that HSP-causing atlastin-1 mutations exhibit a dominant-negative effect on trafficking of BMPRII, which disrupts the BMP pathway in neurons."

A fusion-independent, dominant-negative effect of disease variants on BMP receptor trafficking.

PMID:28240257 SUPPORT In Vitro

"These results suggest that SOCE plays an important role in neuronal regeneration, and mutations in ATL1 may cause HSP, partly by undermining SOCE."

Store-operated calcium entry as a further candidate route from mutant atlastin-1 to neurite growth failure.

Non-cell-autonomous astrocyte cholesterol deficit drives cortical projection neuron degeneration

glial_cholesterol_supply EMERGING

Evidence balance 3 support

Isogenic and patient-derived human pluripotent stem cell models show that ATL1 variants reduce astrocyte lipid-droplet size and cholesterol transfer to neurons, leaving cortical projection neurons cholesterol-deficient, and that cholesterol, control astrocyte medium or LXR agonists rescue axonal transport, swellings and degeneration. The lipid-droplet link follows from atlastin's conserved role in ER fusion, but the human in vivo relevance is untested.

Pathograph links

Impaired Homotypic ER Tubule Fusion -> Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons INDIRECT KNOWN INTERMEDIATES Atlastin-mediated ER fusion sets lipid-droplet size in worm, fly and mammalian cells, and the effect scales with fusion activity; in human ATL1-mutant astrocytes lipid droplets are small and cholesterol export to neurons fails.

Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons -> Impaired Axonal ER Distribution, Organelle Transport and Axon Growth INDIRECT KNOWN INTERMEDIATES Cholesterol deficiency in the projection neuron impairs axonal transport and produces swellings; restoring cholesterol, from any source, rescues them.

Show evidence (3 references)

PMID:33287888 SUPPORT In Vitro

"These results reveal a non-cell autonomous mechanism underlying axonal degeneration of cortical PNs mediated by impaired cholesterol homeostasis in glia."

The stem-cell study that proposes the glial cholesterol mechanism.

PMID:41250225 SUPPORT In Vitro

"LXR623 significantly mitigated the reduction in synaptic proteins and calcium activity and rescued axonal degeneration and apoptosis in SPG3A cortical PNs."

Pharmacological rescue through an LXR agonist that modulates lipid metabolism and transfer.

PMID:42419637 SUPPORT Model Organism

"Models of pure ATL1-HSP display disrupted lipid homeostasis, including lipid droplet accumulation within nerves comprising long motor neuron axons, which is partially ameliorated by treatment with a liver X receptor (LXR) agonist."

In vivo support for a lipid lesion that answers to LXR agonism, in flies carrying pure-HSP patient variants; the lesion is in nerve rather than glia and runs in the opposite direction to the astrocyte droplet phenotype.

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Discussions and Knowledge Gaps

4

Do SPG3A missense variants cause disease by a dominant-negative effect on atlastin-1 oligomers, by simple loss of function with dosage sensitivity, or by allele-specific mechanisms that differ between variants?

CONTROVERSY OPEN controversy_atl1_dominant_negative_vs_loss_of_function

Attached to

pathophysiology#ATL1 Variant Impairing the Atlastin-1 GTPase Cycle genetic#ATL1

Dominant inheritance with a missense-dominated spectrum, mixed-oligomer formation, and dominant-negative disruption of ER reticularisation and BMPRII trafficking in cells support a dominant-negative mechanism. Against it, four patient variants knocked into the endogenous fly gene behave as loss-of-function alleles that do not act as dominant negatives when overexpressed, the most frequently identified variant retains wild-type activity in every assay, one GTPase-domain variant is active while transmembrane variants vary, and homozygous families with asymptomatic heterozygous parents show that ATL1 can also cause recessive, dosage-type disease. The entry records DOMINANT_NEGATIVE as the best-supported category for the typical heterozygous allele but does not treat the question as settled.

Proposed experiments

Heterozygous patient-variant knock-in mice with corticospinal ER ultrastructure

exp_atl1_heterozygous_patient_variant_knockin_mouse

Generate mice heterozygous for frequent human alleles (R239C, R217Q, P342S) on a wild-type Reep1 background, age them, and compare corticospinal axonal ER by FIB-SEM and motor phenotype with heterozygous null and homozygous knock-in littermates. A phenotype in heterozygous missense but not heterozygous null animals would support a dominant-negative mechanism; equivalent phenotypes would support dosage.

Would support

pathophysiology#ATL1 Variant Impairing the Atlastin-1 GTPase Cycle

Supporting outcome

Heterozygous missense knock-in mice develop a corticospinal ER lesion and motor decline that heterozygous null mice do not.

Refuting outcome

Heterozygous missense and heterozygous null mice are indistinguishable, or neither shows a phenotype without Reep1 loss.

Show evidence (5 references)

PMID:16537571 SUPPORT In Vitro

"Here, we demonstrate that several missense SPG3A mutant atlastin-1 proteins have impaired GTPase activity and thus may act in a dominant-negative, loss-of-function manner by forming mixed oligomers with wild-type atlastin-1."

The dominant-negative side.

PMID:33177972 SUPPORT Model Organism

"These results indicate that the four pathological mutations investigated act through a loss of function mechanism."

The loss-of-function side, from patient variants in the endogenous fly gene.

PMID:19573020 SUPPORT In Vitro

"The GTPase mutations T162P and R217C decreased but did not totally prevent this action; the C-terminal transmembrane domain mutation R495W was as active as the wild-type enzyme."

Allele-specific heterogeneity: GTPase-domain variants partially impair membrane remodelling while a transmembrane variant is fully active.

+ 2 more references

What does the tubular ER of a human SPG3A corticospinal axon actually look like, and which downstream consequence of its disruption is the one that kills the distal axon?

KNOWLEDGE GAP OPEN gap_atl1_axonal_er_status_in_patient_corticospinal_neurons

Attached to

pathophysiology#Disrupted Tubular ER Network in Neurons pathophysiology#Impaired Axonal ER Distribution, Organelle Transport and Axon Growth pathophysiology#Distal Length-Dependent Corticospinal Axon Degeneration

Every observation of the ER lesion comes from non-neuronal cells, cultured neurons with short axons, invertebrate neurons or the double-mutant mouse, where the axonal ER expands rather than fragments. No post-mortem ultrastructural study of SPG3A corticospinal axons exists, and the entry's edges from the ER network defect to distal degeneration are therefore inferred. Candidate intermediates that have each been shown in some system (ER-microtubule coupling, mitochondrial distribution, store-operated calcium entry, cholesterol supply, synaptic maintenance) have not been ranked against one another in a long human axon.

Proposed experiments

Volume electron microscopy of SPG3A post-mortem corticospinal tract

exp_spg3a_postmortem_corticospinal_er_ultrastructure

Serial-section or FIB-SEM reconstruction of thoracic corticospinal axons from SPG3A donors compared with age-matched controls and SPG4 donors, scoring axonal ER continuity, transverse expansion, three-way junction density and mitochondrial morphology along the axon.

Would support

pathophysiology#Disrupted Tubular ER Network in Neurons

Supporting outcome

SPG3A corticospinal axons show fragmented or transversely expanded ER with associated mitochondrial change, absent in controls.

Refuting outcome

Axonal ER morphology in SPG3A donors is indistinguishable from controls.

Show evidence (1 reference)

PMID:33287888 SUPPORT In Vitro

"Hereditary spastic paraplegias (HSPs) are caused by a length-dependent axonopathy of long corticospinal neurons, but how axons of these cortical projection neurons (PNs) degenerate remains elusive."

The authors' own statement of the gap this discussion records.

Why do single-gene atlastin-1 loss-of-function animals not reproduce the human early-onset corticospinal syndrome, and how should the fly's dopaminergic neuron loss and the mouse's requirement for Reep1 loss be weighed when using these models for therapy testing?

HUMAN MODEL MISMATCH OPEN mismatch_atl1_rodent_and_fly_models

Attached to

animal_models#Mus musculus animal_models#Drosophila melanogaster pathophysiology#Distal Length-Dependent Corticospinal Axon Degeneration

Mouse HSP models are typically mild and late-onset, plausibly because murine corticospinal axons are far shorter than human ones; a robust motor phenotype required combining a homozygous GTPase-dead Atl1 knock-in with Reep1 loss, a genotype no patient carries. The fly atl null degenerates dopaminergic neurons and becomes paralysed by mechanical shock, neither of which is part of SPG3A, and fly motor neurons are lower motor neurons. Both systems are therefore informative for the ER and transport nodes and much weaker for the corticospinal degeneration and spasticity nodes, and a rescue in either should not be read as evidence about the human axon without a length-dependent readout.

Proposed experiments

Length-dependent readouts in long-axon human systems

exp_atl1_length_dependent_readout_in_long_axon_systems

Use compartmentalised microfluidic cultures or engineered long-axon organoid-spinal assembloids from SPG3A patient and isogenic lines to measure ER continuity, organelle transport and degeneration as a function of distance from the soma, so that candidate therapies (microtubule stabilisers, LXR agonists, BMP modulators) are tested against a length-dependent phenotype rather than a short-axon growth assay.

Would support

pathophysiology#Distal Length-Dependent Corticospinal Axon Degeneration

Supporting outcome

Degeneration and transport failure increase with axon length in SPG3A lines and are corrected by the candidate therapy along the whole axon.

Refuting outcome

Phenotypes are length-independent or absent in long-axon human systems.

Show evidence (2 references)

PMID:35348668 SUPPORT Model Organism

"Typically, mouse models of HSPs have mild, later onset phenotypes, possibly reflecting far shorter lengths of their corticospinal axons relative to humans."

The mouse authors' own account of why single-gene rodent HSP models are mild.

PMID:17030474 SUPPORT Model Organism

"Furthermore, the flies showed age-dependent degeneration of dopaminergic neurons."

The fly phenotype with no human counterpart.

What determines the incomplete penetrance and the wide intrafamilial variability in onset of SPG3A, and are the genetic modifiers found in the fly relevant to patients?

OPEN QUESTION OPEN question_atl1_penetrance_and_modifiers

Attached to

inheritance#Autosomal dominant genetic#ATL1

Asymptomatic carriers are recorded in French, Dutch-German and Russian series, one family with R495W ranged in onset from 8 to 28 years, and the de novo cluster shows that variant position explains part but not all of the severity range. A deficiency screen in the fly identified 35 enhancer and four suppressor regions of the atlastin-knockdown climbing phenotype and a genetic interaction with a Polycomb repressive complex 1 component, suggesting epigenetic modifiers, but no human modifier has been identified. Reduced and sex-dependent penetrance at a mutational hotspot (c.1243C>T and c.1244G>A) made two large ATL1 families look recessive or X-linked, so misread pedigrees are one reason SPG3A is under-ascertained.

Show evidence (3 references)

PMID:23483706 SUPPORT Human Clinical

"A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively)."

Reduced and sex-dependent penetrance at an ATL1 hotspot disguising dominant inheritance.

PMID:17502470 SUPPORT Human Clinical

"We found incomplete penetrance in 1 family (G482V)."

Incomplete penetrance in the 182-family cohort.

PMID:37368047 SUPPORT Model Organism

"We found that atl interacts genetically with Su(z)2, a component of the Polycomb repressive complex 1, suggesting that epigenetic regulation plays a role in the variability of HSP-like phenotypes caused by atl alleles."

The fly modifier screen's lead candidate class.

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Pathophysiology

11

ATL1 Variant Impairing the Atlastin-1 GTPase Cycle

Atlastin-1 is a neuronally enriched, dynamin-like integral-membrane GTPase of the tubular ER, built from an N-terminal GTPase domain, a three-helix bundle, two transmembrane segments and a C-terminal amphipathic tail. GTP-dependent head-to-head dimerisation across apposed membranes, crossover of the three-helix bundles and GTP hydrolysis pull the membranes together. Heterozygous ATL1 missense variants cluster in the GTPase domain and the three-helix bundle and disturb this cycle in allele-specific ways: several reduce GTP hydrolysis and dimerisation, one (F151S) uncouples the catalytic site from nucleotide loading, and others destabilise the GTP-bound crossover dimer or the membrane-embedded helix. Mutant protein forms mixed oligomers with wild-type atlastin-1 and in cells acts in a dominant-negative manner, although in the fly several patient variants behave as plain loss-of-function alleles and biallelic variants cause recessive disease, so the dominant-negative label is recorded here as the best-supported, not the only, mechanism.

Fusion-independent functions of atlastin-1 (BMP receptor trafficking, calcium entry) contribute to axonopathy Impaired atlastin-1 ER tubule fusion disrupts the axonal ER network

corticospinal upper motor neuron CL:0008048

Genetic context ATL1 hgnc:11231 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Dominant-negative is the category with the most direct human-variant evidence (mixed oligomer formation, dominant-negative disruption of ER reticularisation and BMPRII trafficking in cells). Loss of function is supported by CRISPR knock-in flies and by the recessive families, and at least two frequent variants have no measurable functional deficit. See the dominant-negative versus loss-of-function discussion.

endoplasmic reticulum organization (ER-shaping machinery) GO:0007029 ↕ DYSREGULATED

atlastin-1 GTPase activity GO:0003924 ↓ DECREASED

endoplasmic reticulum membrane GO:0005789

Animal models

Drosophila atlastin loss-of-function models Drosophila melanogaster perturbs Patient missense variants introduced into the endogenous fly gene test the functional consequence of each allele in vivo.

Downstream

Impaired Homotypic ER Tubule Fusion The GTPase cycle is what drives fusion, so an allele that blocks GTP hydrolysis or crossover dimerisation cannot support the fusion reaction.

Dysregulated BMP Signalling from Impaired BMPRII Trafficking Mutant atlastin-1 binds BMPRII and, in a dominant-negative manner, blocks its trafficking to the cell surface; this does not require loss of fusion activity.

Show evidence (7 references)

PMID:11685207 SUPPORT Human Clinical

"Here we report the identification of mutations in a newly identified GTPase gene, SPG3A, in ADHSP affected individuals."

The gene discovery establishing that SPG3A is caused by mutations in the atlastin-1 GTPase.

PMID:16537571 SUPPORT In Vitro

"Here, we demonstrate that several missense SPG3A mutant atlastin-1 proteins have impaired GTPase activity and thus may act in a dominant-negative, loss-of-function manner by forming mixed oligomers with wild-type atlastin-1."

Shows impaired GTPase activity of patient variants and the mixed-oligomer basis for a dominant-negative effect.

PMID:21220294 SUPPORT In Vitro

"This mechanism is affected in several mutants associated with HSP, providing insights into disease pathogenesis."

The atlastin-1 crystal structures show that disease variants perturb nucleotide-dependent dimerisation.

+ 4 more references

Impaired Homotypic ER Tubule Fusion

Atlastin-1 drives GTP-dependent homotypic fusion of ER tubules: GTP binding reorients the GTPase domain against the three-helix bundle to permit self-association across membranes, and hydrolysis completes the fusion. Human atlastin-1 catalyses lipid mixing directly once its C-terminal autoinhibition is relieved. SPG3A variants that break any step of this cycle leave apposed tubules tethered but unfused, so the three-way junctions that make the tubular ER a continuous network fail to form.

Impaired atlastin-1 ER tubule fusion disrupts the axonal ER network Non-cell-autonomous astrocyte cholesterol deficit drives cortical projection neuron degeneration

homotypic endoplasmic reticulum membrane fusion GO:0016320 ↓ DECREASED

endoplasmic reticulum membrane GO:0005789

Downstream

Disrupted Tubular ER Network in Neurons Interconnection of ER tubules into a polygonal network depends on atlastin-mediated fusion, so fusion failure leaves long unbranched tubules with few three-way junctions.

Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons Atlastin-mediated ER fusion sets lipid-droplet size in worm, fly and mammalian cells, and the effect scales with fusion activity; in human ATL1-mutant astrocytes lipid droplets are small and cholesterol export to neurons fails.

Show evidence (3 references)

PMID:19633650 SUPPORT In Vitro

"In vitro experiments confirm that Atlastin autonomously drives membrane fusion in a GTP-dependent fashion."

Establishes atlastin as the autonomous, GTP-dependent ER fusogen.

PMID:21930898 SUPPORT In Vitro

"GTP binding induces a conformational change that reorients the GTPase domain relative to the 3HB to permit self-association, but the ability to hydrolyze GTP is required for full fusion, indicating that nucleotide binding and hydrolysis play distinct roles."

The mechanistic sequence, binding then hydrolysis, that disease variants interrupt at different steps.

PMID:34817557 SUPPORT In Vitro

"Here, we report successful reconstitution of fusion activity by the human ATLs. Unexpectedly, the major splice isoforms of ATL1 and ATL2 are each autoinhibited, albeit to differing degrees."

Shows that human atlastin-1 itself, not only the fly orthologue, catalyses fusion, so the human step is real.

Disrupted Tubular ER Network in Neurons

Without atlastin-1-mediated fusion the peripheral ER of the neuron becomes long, unbranched and poorly interconnected: three-way junctions are lost, the network retracts from distal neurites, and ER-microtubule coordination through the atlastin-1, spastin and REEP1 complex is disturbed. In the corticospinal axons of the Atl1 K80A knock-in, Reep1-null mouse the axonal ER instead expands transversely into a periodic ladder-like structure, dosage-dependently, with fragmented mitochondria and hypophosphorylated neurofilaments in lockstep. Whether the ER of patient corticospinal axons shows either change is not known.

Impaired atlastin-1 ER tubule fusion disrupts the axonal ER network

corticospinal upper motor neuron CL:0008048

endoplasmic reticulum tubular network organization GO:0071786 ↓ DECREASED

endoplasmic reticulum tubular network GO:0071782

Animal models

Atl1 K80A knock-in / Reep1 knockout double-mutant mouse Mus musculus partially recapitulates The only in vivo observation of the ER of corticospinal axons under atlastin-1 GTPase loss; the ER is disorganised but expands rather than fragments.

Drosophila atlastin loss-of-function models Drosophila melanogaster recapitulates Loss of the fly atlastin fragments the ER, the defining cellular lesion.

C. elegans atln-1 mutant Caenorhabditis elegans recapitulates In vivo neuronal ER morphology under atlastin loss, with patient alleles tested.

Downstream

Impaired Axonal ER Distribution, Organelle Transport and Axon Growth A fragmented ER cannot be carried into and along the growing axon, and its coupling to microtubules and mitochondria is lost, which is why microtubule-binding agents rescue the axon-growth defect of SPG3A neurons.

Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves In the complicated form the same ER-network lesion is presumed to injure the long peripheral motor and sensory axons, as it does in the allelic disorder HSN1D, but the intermediate steps have not been shown in SPG3A.

Show evidence (5 references)

PMID:19665976 SUPPORT In Vitro

"Since atlastin-1 mutations cause a common form of hereditary spastic paraplegia, we suggest ER-shaping defects as a neuropathogenic mechanism."

Proposes the ER-shaping defect as the neuropathogenic mechanism of SPG3A.

PMID:20200447 SUPPORT In Vitro

"The atlastin-1 GTPase interacts with spastin, a microtubule-severing ATPase, as well as with the DP1/Yop1p and reticulon families of ER-shaping proteins, and SPG3A caused by atlastin-1 mutations has been linked pathogenically to abnormal ER morphology."

Places atlastin-1 in the spastin and REEP1 ER-shaping complex and links SPG3A to abnormal ER morphology.

PMID:27669642 SUPPORT In Vitro

"ER morphology is markedly disrupted in these triple KO cells, with prominent impairment in formation of three-way ER tubule junctions."

Mammalian cells lacking all three atlastins lose three-way junctions, the specific network defect of atlastin loss.

+ 2 more references

Dysregulated BMP Signalling from Impaired BMPRII Trafficking

Atlastin-1 binds the type II BMP receptor and inhibits BMP signalling, in concert with the other HSP proteins spastin, NIPA1 and spartin. Patient variants R239C and R495W block BMPRII trafficking to the cell surface in a dominant-negative manner and blunt Smad1/5 phosphorylation after BMP4, whereas knockdown of atlastin in zebrafish substantially up-regulates BMP signalling and disorganises spinal motor axons. The direction of the change therefore differs between the human dominant-negative variants and loss-of-function models, which is why the process is recorded as dysregulated rather than increased or decreased.

Fusion-independent functions of atlastin-1 (BMP receptor trafficking, calcium entry) contribute to axonopathy

motor neuron CL:0000100

BMP signaling pathway GO:0030509 ↕ DYSREGULATED

Animal models

Zebrafish atl1 morphant Danio rerio partially recapitulates Establishes atlastin as a negative regulator of BMP signalling in vertebrate motor neurons and shows that BMP dysregulation is sufficient to disturb motor axon architecture.

Downstream

Impaired Axonal ER Distribution, Organelle Transport and Axon Growth BMP signalling tunes motor axon architecture; in atlastin-depleted zebrafish, inhibiting BMP signalling is sufficient to rescue the motor axon defects, so the BMP arm feeds into the axonal phenotype.

Show evidence (3 references)

PMID:23079343 SUPPORT In Vitro

"Expression of mutant forms of atlastin-1 also interfered with the signaling response to BMP4 stimulation and reduced phosphorylation of Smad 1/5 proteins."

Patient variants blunt the BMP4 signalling response in cells.

PMID:20935645 SUPPORT Model Organism

"We found that knockdown of the gene for atlastin (atl1) caused a severe decrease in larval mobility that was preceded by abnormal architecture of spinal motor axons and was associated with a substantial upregulation of the bone morphogenetic protein (BMP) signaling pathway."

Atlastin loss in zebrafish up-regulates BMP signalling, the opposite direction from the cell data, hence the dysregulated modifier.

PMID:30082270 SUPPORT Model Organism

"We next showed that M1 spastin, together with HSP proteins atlastin 1 and NIPA1, drives motor axon targeting by repressing BMP signalling"

Places atlastin-1 in a shared HSP-protein module that represses BMP signalling in vertebrate motor axons.

Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons

ATL1 variants in human pluripotent stem cell-derived astrocytes dysregulate proteolipid gene expression, shrink lipid droplets and disrupt cholesterol transfer to neurons, leaving co-cultured cortical projection neurons cholesterol-deficient. This is a non-cell-autonomous arm: the neuronal axonal defects are rescued by exogenous cholesterol, by conditioned medium from control astrocytes, or by liver-X-receptor agonists that restore astrocyte cholesterol efflux.

Non-cell-autonomous astrocyte cholesterol deficit drives cortical projection neuron degeneration

astrocyte CL:0000127

cholesterol transport from astrocytes to neurons GO:0030301 ↓ DECREASED

Experimental models

Isogenic hPSC ATL1 A161P and patient P342S cortical projection neurons with astrocytes IPSC DERIVED MODEL The model in which the astrocyte lipid-droplet and cholesterol-transfer defect was discovered and rescued.

Animal models

Drosophila atlastin loss-of-function models Drosophila melanogaster partially recapitulates Flies carrying pure-HSP patient-variant homologues show disrupted lipid homeostasis in long motor nerves that is partially corrected by an LXR agonist, the same pharmacology that rescues the human stem-cell lipid phenotype.

Downstream

Impaired Axonal ER Distribution, Organelle Transport and Axon Growth Cholesterol deficiency in the projection neuron impairs axonal transport and produces swellings; restoring cholesterol, from any source, rescues them.

Show evidence (2 references)

PMID:33287888 SUPPORT In Vitro

"Importantly, ATL1 mutations dysregulated proteolipid gene expression, reduced lipid droplet size in astrocytes, and unexpectedly disrupted cholesterol transfer from glia to neurons, leading to cholesterol deficiency in SPG3A cortical PNs."

The core observation of the astrocyte lipid-droplet and cholesterol-transfer defect in human ATL1-mutant cells.

PMID:23684613 SUPPORT Model Organism

"Using genetic screens in C. elegans for LD morphology defects in intestinal cells, we found that mutations in atlastin, a GTPase required for homotypic fusion of endoplasmic reticulum (ER) membranes, cause not only ER morphology defects, but also a reduction in LD size."

The conserved atlastin lipid-droplet function from which the astrocyte defect follows.

Impaired Axonal ER Distribution, Organelle Transport and Axon Growth

Atlastin-1 is enriched in growth cones, axonal varicosities and branch points of cortical neurons, and its knockdown or mutation reduces axon formation and elongation. Human SPG3A neurons show impaired axon growth, altered mitochondrial motility, impaired axonal transport and axonal swellings, and dominant-negative ATL1 blocks NGF-driven neurite outgrowth in PC-12 cells partly by undermining store-operated calcium entry. In the double-mutant mouse, axonal mitochondria fragment and neurofilament H and M become hypophosphorylated in lockstep with the ER change. Because SPG3A begins so early, a developmental component to the axonopathy has been proposed alongside failure of maintenance.

corticospinal upper motor neuron CL:0008048

axon extension GO:0048675 ↓ DECREASED axonal transport GO:0098930 ↓ DECREASED mitochondrion organization GO:0007005 ↕ DYSREGULATED

Experimental models

SPG3A patient iPSC-derived forebrain neurons (ATL1 p.Pro342Ser) IPSC DERIVED MODEL Patient neurons show impaired axon growth and altered mitochondrial motility, and the growth defect is rescued by microtubule-binding agents.

Isogenic hPSC ATL1 A161P and patient P342S cortical projection neurons with astrocytes IPSC DERIVED MODEL Reduced axonal outgrowth, impaired axonal transport and axonal swellings in cortical projection neurons.

Downstream

Presynaptic Dysfunction of Corticospinal Neurons Failure to deliver secretory organelles and presynaptic components along the axon depletes the terminal, as shown for fly motor neurons.

Distal Length-Dependent Corticospinal Axon Degeneration Chronic failure of organelle and membrane supply is the proposed route to distal degeneration of the longest axons; the terminal injury pathway in human corticospinal axons is inferred rather than observed.

Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves Patient iPSC-derived lower motor neurons carry the same axonal swellings and form fewer, simpler neuromuscular junctions, which is the in vitro correlate of the peripheral arm seen in the complicated form.

Show evidence (7 references)

PMID:16537571 SUPPORT In Vitro

"Indeed, knock-down of atlastin-1 expression in these neurons using small hairpin RNAs reduces the number of neuronal processes and impairs axon formation and elongation during development."

Atlastin-1 loss impairs axon formation and elongation in cortical neurons.

PMID:24908668 SUPPORT In Vitro

"Axons of these SPG3A neurons showed impaired growth, recapitulating axonal defects in atlastin-1-depleted rat cortical neurons and impaired root hair growth in loss-of-function mutants of the ATL1 ortholog rhd3 in the plant Arabidopsis."

Patient iPSC-derived neurons reproduce the axon-growth defect.

PMID:24908668 SUPPORT In Vitro

"SPG3A neurons showed alterations in mitochondrial motility."

Mitochondrial motility is altered in the same neurons, the organelle-distribution part of this node.

+ 4 more references

Presynaptic Dysfunction of Corticospinal Neurons

Transcriptomic comparison of SPG3A patient iPSC-derived cortical projection neurons with controls identifies synaptic dysfunction as a top altered pathway beside lipid pathways: synaptic genes and proteins are reduced and calcium activity is diminished in neurons from two patients with different missense variants, and both are restored by the LXR agonist LXR623. In fly motor neurons, atlastin loss depletes presynaptic proteins at terminals and disturbs synaptic vesicle pools, with progressive decline in locomotion.

corticospinal upper motor neuron CL:0008048

synapse organization GO:0050808 ↓ DECREASED

Experimental models

SPG3A patient iPSC-derived cortical projection neurons (P342S and M408T) IPSC DERIVED MODEL Synaptic gene and protein loss and reduced calcium activity in patient neurons from two variants, rescued by an LXR agonist.

Animal models

Drosophila atlastin loss-of-function models Drosophila melanogaster partially recapitulates Motor-neuron atlastin loss depletes presynaptic terminals and disturbs synaptic vesicle pools, with progressive locomotor decline.

Downstream

Distal Length-Dependent Corticospinal Axon Degeneration Synaptic failure and degeneration co-occur in the patient neuron model and are rescued together, but whether synaptic dysfunction precedes or follows axonal degeneration has not been resolved.

Show evidence (3 references)

PMID:41250225 SUPPORT In Vitro

"We observed significant reductions of synaptic genes and proteins in cortical PNs from both SPG3A-P342S and SPG3A-M408T patient iPSCs, emphasizing synaptic dysfunction in SPG3A neurons."

Synaptic gene and protein loss in patient cortical projection neurons carrying two different variants.

PMID:41250225 SUPPORT In Vitro

"Calcium imaging revealed a significant reduction of activity in SPG3A cortical neurons compared to control neurons, further supporting functional deficits in SPG3A neurons."

The functional correlate of the synaptic protein loss.

PMID:28860117 SUPPORT Model Organism

"Using Drosophila, we demonstrate that downregulation or overexpression of Atlastin in motor neurons results in decreased crawling speed and contraction frequency in larvae, while adult flies show progressive decline in climbing ability."

Motor-neuron atlastin loss produces a progressive locomotor decline with presynaptic dysfunction in the fly.

Distal Length-Dependent Corticospinal Axon Degeneration

The corticospinal axons reaching the lumbosacral cord, the longest in the central nervous system, degenerate from their distal ends in a retrograde, length-dependent pattern, so the deficit is maximal in the legs and the arms are largely spared. In SPG3A the corticospinal lesion is clinically evident from early childhood and is reflected in frequently abnormal motor evoked potentials, while the dorsal columns are involved in only a minority. Quantitative post-mortem study of HSP shows reduced corticospinal axon number at every level with the loss most pronounced distally, the signature of a dying-back axonopathy.

corticospinal upper motor neuron CL:0008048

neuron projection maintenance GO:1990535 ↓ DECREASED

Downstream

Loss of Supraspinal Inhibition of the Spinal Stretch Reflex

Show evidence (5 references)

PMID:15540998 SUPPORT INDIRECT Human Clinical

"In the corticospinal tracts, the ratio of medulla and lumbar total axonal number was significantly greater in HSP cases compared to controls suggesting more pronounced axonal loss in the distal neuraxis in HSP than in controls."

The quantitative human neuropathology of the length-dependent corticospinal lesion; from six HSP post-mortems of unspecified genotype, so indirect for SPG3A.

PMID:15540998 SUPPORT INDIRECT Human Clinical

"These findings are consistent with a length-dependent 'dying back' axonopathy."

The pathologists' own reading of the pattern as a dying-back axonopathy.

PMID:18270207 SUPPORT In Vitro

"The hereditary spastic paraplegias (SPG1-33) comprise a cluster of inherited neurological disorders characterized principally by lower extremity spasticity and weakness due to a length-dependent, retrograde axonopathy of corticospinal motor neurons."

States the length-dependent retrograde corticospinal axonopathy shared by the HSPs; cited as the framing of the SPG3A study rather than as a primary pathological observation.

+ 2 more references

Loss of Supraspinal Inhibition of the Spinal Stretch Reflex

Loss of descending corticospinal input releases the lumbar stretch reflex from supraspinal inhibitory control, producing velocity-dependent hypertonia, hyperreflexia, clonus and extensor plantar responses. The step is the shared HSP mechanism carried by the module and is not separately evidenced for SPG3A.

spinal motor neuron CL:0000100

Downstream

Progressive Lower-Limb Spasticity and Weakness

Bilateral, largely symmetric spasticity and weakness of the legs presenting as a spastic gait, usually in the first decade, with slow and often near-static progression in SPG3A and preserved ambulation in most.

Animal models

Atl1 K80A knock-in / Reep1 knockout double-mutant mouse Mus musculus partially recapitulates Early-onset, rapidly progressive motor decline on several tests, as a correlate of the human motor syndrome.

Downstream

Spastic gait

Lower limb spasticity

Lower limb muscle weakness

Show evidence (2 references)

PMID:20862796 SUPPORT Human Clinical

"Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs."

GeneReviews clinical characterization of the core syndrome.

PMID:39003427 SUPPORT Human Clinical

"Individuals with SPG3A typically present a slow progression and remain ambulatory throughout their life."

The typical slow course with preserved ambulation.

Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves

In the complicated form, and subclinically in further patients, the long peripheral motor and sensory axons also degenerate, producing an axonal sensorimotor neuropathy with lower motor neuron involvement and distal amyotrophy. This is the peripheral counterpart of the corticospinal lesion, conforming to the peripheral module at its axonal-degeneration node; there is no demyelinating component. The allelic disorder HSN1D shows that ATL1 variants can injure long peripheral axons on their own.

lower motor neuron CL:0008039

Experimental models

Autologous iPSC-derived lower motor neuron and myotube neuromuscular junction co-culture CO CULTURE Patient lower motor neurons show axonal swellings and form fewer, less complex neuromuscular junctions, a correlate of the lower motor neuron arm of the complicated form.

Downstream

Distal amyotrophy

Peripheral axonal neuropathy

Show evidence (2 references)

PMID:17502470 SUPPORT Human Clinical

"Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy."

Electrophysiology and nerve pathology establish the peripheral lesion as axonal and sensorimotor.

PMID:25193411 SUPPORT Human Clinical

"Electrophysiological studies revealed severe diffuse axonal neuropathy."

A severe complicated case with diffuse axonal neuropathy.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

21

Digestive 2

Pseudobulbar paralysis VERY_RARE HP:0007024

Show evidence (1 reference)

PMID:25193411 SUPPORT Human Clinical

"He also developed with pseudobulbar palsy; his speech, chewing, and swallowing were severely impaired."

Pseudobulbar palsy in the neonatal-onset G409D case.

Dysphagia VERY_RARE HP:0002015

Show evidence (1 reference)

PMID:39003427 SUPPORT Human Clinical

"In conclusion, we report here the cases of 3 patients with severe forms of early-onset SPG3A, offering detailed descriptions of this poorly known phenotype made of neonatal hypotonia, secondary limbs spasticity (spastic para or tetraplegia), developmental delay, speech and swallowing problems."

Swallowing problems in the authors' summary of the severe phenotype; quoted from the full text.

Genitourinary 1

Urinary urgency OCCASIONAL HP:0000012

Show evidence (1 reference)

PMID:20862796 SUPPORT Human Clinical

"Compared to other forms of autosomal dominant hereditary spastic paraplegia (HSP), in which diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns) and urinary bladder hyperactivity are present in all affected individuals, these findings occur in a..."

GeneReviews places bladder hyperactivity in a minority of SPG3A cases.

Limbs 2

Lower limb muscle weakness VERY_FREQUENT HP:0007340

Show evidence (1 reference)

PMID:20862796 SUPPORT Human Clinical

"Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs."

GeneReviews pairs weakness with spasticity in the core description.

Foot dorsiflexor weakness FREQUENT HP:0009027

Show evidence (1 reference)

PMID:20862796 SUPPORT Human Clinical

"Distal weakness (typically affecting foot dorsiflexion) can be ameliorated by ankle-foot orthoses."

GeneReviews identifies foot dorsiflexion as the typical site of distal weakness.

Musculoskeletal 6

Lower limb spasticity VERY_FREQUENT HP:0002061

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20862796 SUPPORT Human Clinical

"Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs."

GeneReviews names lower-limb spasticity as the defining feature.

Spastic gait VERY_FREQUENT HP:0002064

Onset: CHILDHOOD; mean 4y

Show evidence (4 references)

PMID:20862796 SUPPORT Human Clinical

"The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life."

GeneReviews onset figures for the presenting spastic gait.

PMID:16401858 SUPPORT Human Clinical

"SPG3A was twice as frequent as SPG4 in patients with onset before age 10 years (31.8%). Later onset was not observed."

In the German cohort every SPG3A case began before age ten.

PMID:17502470 SUPPORT Human Clinical

"In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y)."

Records both the typical early onset and a later-onset family with intrafamilial variability.

+ 1 more reference

Scoliosis OCCASIONAL HP:0002650

Show evidence (1 reference)

PMID:15596607 SUPPORT Human Clinical

"However, additional signs such as decreased vibration sense and wasting in lower limbs, sphincter disturbances, and scoliosis were found in a minority of patients."

Scoliosis in a minority of the French SPG3A patients.

Distal amyotrophy OCCASIONAL HP:0003693

Show evidence (2 references)

PMID:20862796 SUPPORT Human Clinical

"complicated HSP with axonal motor neuropathy and/or distal amyotrophy with lower motor neuron involvement (Silver syndrome phenotype) has been observed."

GeneReviews documents distal amyotrophy in the complicated phenotype.

PMID:22378671 SUPPORT Human Clinical

"At the last neurologic examination performed at 17 years of life, the patient disclosed spastic tetraparesis, sensorimotor axonal neuropathy, cognitive and cranial nerve impairment, mild pes cavus, and distal amyotrophy."

Distal amyotrophy in a severe complicated case.

Axial hypotonia VERY_RARE HP:0008936

Onset: INFANTILE

Show evidence (1 reference)

PMID:39003427 SUPPORT Human Clinical

"Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability)."

Axial hypotonia in the three very-early-onset cases.

Spastic tetraplegia VERY_RARE HP:0002510

Show evidence (2 references)

PMID:39003427 SUPPORT Human Clinical

"Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability)."

Spastic quadriplegia in the very-early-onset cases.

PMID:22378671 SUPPORT Human Clinical

"At the last neurologic examination performed at 17 years of life, the patient disclosed spastic tetraparesis, sensorimotor axonal neuropathy, cognitive and cranial nerve impairment, mild pes cavus, and distal amyotrophy."

Spastic tetraparesis in a P344S very-early-onset case.

Nervous System 10

Hyperreflexia HP:0001347

Show evidence (2 references)

PMID:34831093 SUPPORT INDIRECT Other

"The severity of these symptoms varies among patients, and they are often accompanied by lower-extremity hyperreflexia and extensor plantar responses."

A statement about HSP in general, applied to SPG3A as a pure HSP; the quote is from the full text of a review rather than an SPG3A cohort.

PMID:15596607 SUPPORT Human Clinical

"SPG3A patients had earlier symptom onset, less frequently increased reflexes in the upper limbs, decreased vibration sense in the lower limbs, and fewer sphincter disturbances, but more frequently observed wasting in the lower limbs and scoliosis."

The comparison with SPG4 that distinguishes the SPG3A reflex pattern.

Babinski sign HP:0003487

Show evidence (1 reference)

PMID:34831093 SUPPORT INDIRECT Other

"The severity of these symptoms varies among patients, and they are often accompanied by lower-extremity hyperreflexia and extensor plantar responses."

A general HSP statement applied to SPG3A as a pure HSP; quoted from the review's full text.

Abnormal motor evoked potentials FREQUENT HP:0012896

Show evidence (1 reference)

PMID:15596607 SUPPORT Human Clinical

"These particularities, as well as frequent abnormal motor evoked potentials, could help identify patients to be screened for atlastin1 gene mutations."

The French series reports frequent abnormal motor evoked potentials in SPG3A.

Impaired vibratory sensation OCCASIONAL HP:0002495

Show evidence (2 references)

PMID:20862796 SUPPORT Human Clinical

"Compared to other forms of autosomal dominant hereditary spastic paraplegia (HSP), in which diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns) and urinary bladder hyperactivity are present in all affected individuals, these findings occur in a..."

GeneReviews places dorsal-column sensory loss in a minority of SPG3A cases.

PMID:15596607 SUPPORT Human Clinical

"However, additional signs such as decreased vibration sense and wasting in lower limbs, sphincter disturbances, and scoliosis were found in a minority of patients."

The French series confirms decreased vibration sense in a minority.

Peripheral axonal neuropathy OCCASIONAL HP:0003477

Show evidence (2 references)

PMID:17502470 SUPPORT Human Clinical

"Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy."

Frequency and axonal sensorimotor character of the neuropathy.

PMID:19735987 SUPPORT Human Clinical

"We report a new heterozygous S398F mutation in exon 12 of the SPG3A gene causing a very early-onset spastic paraplegia in association with motor axonal neuropathy in a 4-year-old girl resembling diplegic cerebral palsy."

A de novo case with motor axonal neuropathy that mimicked cerebral palsy.

Dystonia HP:0001332

Show evidence (1 reference)

PMID:41328529 SUPPORT Human Clinical

"Distinct genotype-specific patterns were observed: dystonia in SPG4, SPG3A, and AP-4-HSP; parkinsonism in SPG11; and ataxia in SPG15, SPG76, SPG7, SPG5a, and SPG46."

A 428-case natural-history study associates dystonia with the SPG3A genotype; frequency within SPG3A is not given, so none is recorded.

Intellectual disability VERY_RARE HP:0001249

Show evidence (2 references)

PMID:39003427 SUPPORT Human Clinical

"Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability)."

Intellectual disability in the very-early-onset cases.

PMID:37927245 SUPPORT Human Clinical

"The infant's phenotype is consistent with an early onset complicated SPG3A with severe progressive spasticity of the lower limbs and intellectual disability."

Intellectual disability in a homozygous splice-variant case.

Seizure VERY_RARE HP:0001250

Show evidence (1 reference)

PMID:39003427 SUPPORT Human Clinical

"Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability)."

Seizures in the very-early-onset cases.

Dysarthria VERY_RARE HP:0001260

Show evidence (1 reference)

PMID:39003427 SUPPORT Human Clinical

"Similarly to previous patients, he also presented with swallowing problems and dysarthria."

Dysarthria in the third very-early-onset case; quoted from the full text.

Abnormal cerebral white matter morphology VERY_RARE HP:0002500

Show evidence (2 references)

PMID:39003427 SUPPORT Human Clinical

"Indeed, brain MRI at 5 years revealed white matter T2 hyperintensities evocative of myelination delay"

The imaging finding in the second very-early-onset case; quoted from the full text.

PMID:35925862 SUPPORT Human Clinical

"Establishing genotype-phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with..."

Brain imaging abnormalities are part of the cluster phenotype across 537 cases.

🧬

Genetic Associations

1

ATL1

Gene: ATL1 hgnc:11231 relationship_type: CAUSATIVE

Show evidence (6 references)

PMID:20862796 SUPPORT Human Clinical

"The diagnosis of ATL1-HSP is established in a proband with suggestive findings and almost exclusively a heterozygous pathogenic variant in ATL1 identified by molecular genetic testing."

GeneReviews establishes heterozygous ATL1 variants as the molecular basis.

PMID:15596607 SUPPORT Human Clinical

"So far, most mutations have been private, although they were all found in exons 7, 8, 12, and 13."

Private missense variants clustered in four exons in the French series.

PMID:31594988 SUPPORT Human Clinical

"All 10 detected ATL1 mutations were missense substitutions, most of which were in the mutational hot spots of 4, 7, 8, 12 exons, with 2 novel mutations."

The Russian cohort confirms an all-missense spectrum in the same hotspot exons.

+ 3 more references

Variants (5)

p.Arg239Cys (R239C)

The most frequently identified SPG3A variant, recurring across European and East Asian cohorts. It disrupts BMPRII trafficking in a dominant-negative manner, yet shows wild-type ER network formation, GTPase activity, dimerisation and membrane fusion in every assay, which is the principal evidence that a fusion deficit is not required for disease.

Show evidence (3 references)

PMID:25761634 SUPPORT In Vitro

"Surprisingly however, at least two disease variants, one of which represents that most frequently identified in SPG3A HSP patients, displayed wild-type levels of activity in all assays."

The most frequent variant retains full activity in cell-based and biochemical assays.

PMID:23079343 SUPPORT In Vitro

"Endogenous and expressed atlastin-1 showed a strong interaction with BMP receptors II (BMPRII) and analyzed missense, HSP-causing mutations R239C and R495W disrupted BMPRII trafficking to the cell surface."

The same variant has a measurable fusion-independent effect on BMPRII trafficking.

PMID:34015694 SUPPORT Human Clinical

"Five heterozygous ATL1 mutations were identified, including p.R239C, p.V253I, p.Y336H, p.P342R and p.R416C."

R239C recurs in the Taiwanese cohort.

p.Arg416Cys (R416C), Taiwanese founder allele

The most common ATL1 variant in Taiwan, found in five pedigrees sharing a haplotype consistent with a common ancestor.

Show evidence (1 reference)

PMID:34015694 SUPPORT Human Clinical

"ATL1 p.R416C was the most common mutation and presented in five SPG3A pedigrees. Haplotype analyses demonstrated a shared haplotype in the 12 individuals carrying a p.R416C allele."

Founder evidence from shared haplotype analysis.

p.Arg118Gln (R118Q), homozygous

A homozygous GTPase-domain missense variant segregating with early-onset HSP in six members of a consanguineous family; seven heterozygous carriers were clinically unaffected.

Show evidence (1 reference)

PMID:24473461 SUPPORT Human Clinical

"Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members."

The first recessive SPG3A allele.

p.Pro342Ser (P342S)

A variant in the hinge between the GTPase and assembly domains, found in a girl with pure SPG3A and used to derive the first SPG3A patient iPSC neuronal model; the same patient line underlies the later lipid and synaptic studies.

Show evidence (1 reference)

PMID:24908668 SUPPORT Human Clinical

"We have identified a p.Pro342Ser mutation in a young girl with pure SPG3A. This residue is in a critical hinge region of atlastin-1 between its GTPase and assembly domains, and it is conserved in all known eukaryotic atlastin orthologs."

Identifies the variant, its location and its conservation.

p.Lys406Glu (K406E), de novo

A de novo three-helix-bundle variant in one of the three very-early-onset severe complex cases.

Show evidence (1 reference)

PMID:39003427 SUPPORT Human Clinical

"These individuals carried novel ATL1 pathogenic variants (a de novo ATL1 missense p.(Lys406Glu), a homozygous frameshift p.(Arg403Glufs*3) and a homozygous missense variant (p.Tyr367His))."

The de novo variant among the severe cases.

💊

Medical Actions

7

Oral antispasticity pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: baclofen CHEBI:2972 tizanidine CHEBI:63629

Platform: Small molecule

Treatment is symptomatic. Medical treatment of spasticity begins with oral baclofen or tizanidine. Dantrolene should be avoided because it can induce irreversible weakness that adversely affects mobility. Across HSP there is no specific therapy and the evidence base for symptomatic drugs is thin; the one well-designed antispastic trial, of gabapentin, was negative.

Mechanism Target:

Loss of Supraspinal Inhibition of the Spinal Stretch Reflex — Baclofen and tizanidine dampen the disinhibited spinal stretch reflex rather than acting on the axonopathy.

Target Phenotypes: Lower limb spasticity HP:0002061

Show evidence (4 references)

PMID:20862796 SUPPORT Human Clinical

"Treatment is symptomatic. Medical treatment of spasticity may begin with oral baclofen or tizanidine"

GeneReviews first-line antispasticity recommendation.

PMID:20862796 SUPPORT Human Clinical

"Agents/circumstances to avoid: Dantrolene, as it can induce irreversible weakness, adversely affecting mobility."

GeneReviews drug-safety warning reflected in the treatment description.

PMID:30723448 SUPPORT Human Clinical

"There currently exist no specific therapies for HSP, and treatment is exclusively symptomatic, aimed at reducing muscle spasticity, and improving strength and gait."

The systematic review's framing that all HSP treatment is symptomatic.

+ 1 more reference

Botulinum toxin chemodenervation

Action: Pharmacotherapy NCIT:C15986

Agent: botulinum toxin type A (or type B) CHEBI:3160

Platform: Peptide

Chemodenervation with botulinum A or B toxin is the next step for focal spasticity when oral antispasticity medications are not tolerated.

Target Phenotypes: Lower limb spasticity HP:0002061

Show evidence (1 reference)

PMID:20862796 SUPPORT Human Clinical

"followed by chemodenervation with botulinum A or B toxins if oral antispasticity medications are not tolerated."

GeneReviews second-line recommendation.

Intrathecal baclofen pump

Action: intrathecal baclofen pump therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: baclofen CHEBI:2972

Platform: Device

An intrathecal baclofen pump may be considered for individuals who improve on oral baclofen but have significant systemic adverse effects.

Target Phenotypes: Lower limb spasticity HP:0002061

Show evidence (1 reference)

PMID:20862796 SUPPORT Human Clinical

"Intrathecal baclofen pump may be considered for those who improve on oral baclofen but have significant systemic adverse effects."

GeneReviews indication for the intrathecal route.

Physical therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Medical therapy is combined with intensive physical therapy focused on stretching and strengthening exercises, which may help delay or minimise muscle-tendon contractures, scoliosis and foot deformities.

Target Phenotypes: Lower limb spasticity HP:0002061 Scoliosis HP:0002650

Show evidence (1 reference)

PMID:20862796 SUPPORT Human Clinical

"Medical therapy should be combined with intensive physical therapy focused on stretching and strengthening exercises that may help delay or minimize muscle tendon contractures, scoliosis, and foot deformities."

GeneReviews physical-therapy recommendation and its intended targets.

Ankle-foot orthoses

Action: ankle-foot orthosis fitting Ontology label: Rehabilitation NCIT:C15315

Platform: Device

Distal weakness, typically of foot dorsiflexion, is ameliorated by ankle-foot orthoses.

Target Phenotypes: Foot dorsiflexor weakness HP:0009027

Show evidence (1 reference)

PMID:20862796 SUPPORT Human Clinical

"Distal weakness (typically affecting foot dorsiflexion) can be ameliorated by ankle-foot orthoses."

GeneReviews orthotic recommendation.

Anticholinergic antispasmodic pharmacotherapy for urinary urgency

Action: Pharmacotherapy NCIT:C15986

Agent: anticholinergic agent NCIT:C66880

Platform: Small molecule

Urinary urgency, present in a minority, is treated with anticholinergic antispasmodic drugs.

Target Phenotypes: Urinary urgency HP:0000012

Show evidence (1 reference)

PMID:20862796 SUPPORT Human Clinical

"Urinary urgency can be treated with anticholinergic antispasmodic drugs."

GeneReviews bladder recommendation.

Genetic counselling and surveillance

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Once the familial ATL1 variant is known, prenatal and preimplantation genetic testing are possible; counselling must address incomplete penetrance, de novo variants and the rare recessive form. Reevaluation once or twice yearly to identify and treat new complications is recommended.

Show evidence (2 references)

PMID:20862796 SUPPORT Human Clinical

"prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible."

GeneReviews reproductive options once the familial variant is known.

PMID:20862796 SUPPORT Human Clinical

"reevaluation once or twice yearly to identify and treat new complications is recommended."

GeneReviews surveillance recommendation.

🔬

Diagnosis

4

Molecular genetic testing for ATL1

The diagnosis is established in a proband with suggestive findings by identifying a heterozygous pathogenic ATL1 variant, almost exclusively; biallelic variants are the rare exception. In practice testing is by a multigene HSP panel or exome, since the pure early-onset phenotype overlaps with SPG4 and the severe complex phenotype with cerebral palsy. Directed single-gene screening should be used with caution because recessive families exist.

molecular genetic testing NCIT:C15709

Show evidence (2 references)

PMID:20862796 SUPPORT Human Clinical

"The diagnosis of ATL1-HSP is established in a proband with suggestive findings and almost exclusively a heterozygous pathogenic variant in ATL1 identified by molecular genetic testing."

The GeneReviews confirmatory-testing criterion.

PMID:24473461 SUPPORT Human Clinical

"This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP."

The recessive family's authors warn against pedigree-directed screening.

Electromyography and nerve conduction studies

Electrophysiology detects the axonal sensorimotor neuropathy of the complicated form, including subclinical involvement, and grades its severity in the complex cases.

electromyography and nerve conduction studies NCIT:C38056

Show evidence (2 references)

PMID:17502470 SUPPORT Human Clinical

"Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy."

Electrophysiology is how the neuropathy was characterised.

PMID:25193411 SUPPORT Human Clinical

"Electrophysiological studies revealed severe diffuse axonal neuropathy."

Electrophysiology grading the neuropathy in a severe case.

Brain MRI

Brain MRI is normal in typical pure SPG3A and serves to exclude structural, inflammatory and demyelinating mimics; in a young child labelled cerebral palsy, the absence of MRI changes congruent with that diagnosis is what should prompt genetic testing. In the severe complex form MRI may show white matter T2 hyperintensities with delayed myelination.

brain magnetic resonance imaging NCIT:C16809

Show evidence (2 references)

PMID:39003427 SUPPORT Human Clinical

"Similarly to patient 1, this individual was first diagnosed with CP until follow-up in an expert center and the lack of congruent brain MRI abnormalities motivated further tests."

MRI incongruent with cerebral palsy as the trigger for genetic testing; quoted from the full text.

PMID:39003427 SUPPORT Human Clinical

"Brain MRI performed at the age of 2 years was normal."

A normal MRI in one severe case, so a normal scan does not exclude SPG3A; quoted from the full text.

Motor evoked potentials

Transcranial magnetic stimulation motor evoked potentials are frequently abnormal and were proposed, together with the clinical particularities, as a way to select young-onset dominant HSP patients for ATL1 testing.

motor evoked potentials

Show evidence (1 reference)

PMID:15596607 SUPPORT Human Clinical

"These particularities, as well as frequent abnormal motor evoked potentials, could help identify patients to be screened for atlastin1 gene mutations."

Motor evoked potentials as a screening aid for SPG3A.

📊

Prevalence

1

Worldwide

Unknown Rare

No population prevalence has been measured for SPG3A itself. Autosomal dominant HSP as a whole has a pooled prevalence of 1.8 per 100,000 (range 0.5 to 5.5), and SPG3A is the second most common dominant form in every population studied, accounting for about 5% of dominant HSP in a 13,570-patient meta-analysis, 8 to 10% of familial dominant HSP on average across the literature, and 39% of young-onset dominant families once SPG4 is excluded. Its share therefore places it well below 1 per 100,000, but the figure is derived rather than measured and is deliberately not recorded as a rate.

Show evidence (4 references)

PMID:24603320 SUPPORT Human Clinical

"The prevalence of autosomal dominant (AD) HSP (AD-HSP) ranged from 0.5 to 5.5/10(5) and that of AR-HSP from 0.0 to 5.3/10(5), with pooled averages of 1.8/10(5) (95% CI: 1.0-2.7/10(5)) and 1.8/10(5) (95% CI: 1.0-2.6/10(5)), respectively."

The pooled prevalence of the dominant HSP group of which SPG3A is a fraction.

PMID:24603320 SUPPORT Human Clinical

"The most common AD-HSP form in every population was spastic paraplegia, autosomal dominant, type 4 (SPG4), followed by SPG3A"

Places SPG3A second among dominant HSPs across populations.

PMID:31745725 SUPPORT Human Clinical

"The frequency of mutations in SPAST (25%) was higher than REEP1 (3%), as well as ATL1 (5%) in AD-HSP patients."

The pooled ATL1 share of dominant HSP across 147 studies.

+ 1 more reference

⚖️

Clinical Burden

Variable

Typical SPG3A is mild to moderate: progression is slow, wheelchair dependence is relatively rare, and early-onset HSP in general keeps independent walking longer than later-onset disease. But because onset is so early the cumulative disease duration is long and the eventual handicap can exceed that of other dominant HSPs, and the severe very-early-onset complex subtype rarely achieves independent ambulation.

Show evidence (4 references)

PMID:20862796 SUPPORT Human Clinical

"The rate of progression in ATL1-HSP is slow, and wheelchair dependency or need for a walking aid (cane, walker, or wheelchair) is relatively rare."

GeneReviews on the slow course and preserved ambulation of typical SPG3A.

PMID:26856398 SUPPORT Human Clinical

"Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent."

In the 608-patient German cohort early onset, the SPG3A hallmark, predicts a milder course.

PMID:16401858 SUPPORT Human Clinical

"The phenotype was pure HSP, but disease duration was longer than in non-SPG3A/SPG4 patients, leading ultimately to greater handicap."

The counterweight: long disease duration from early onset accumulates handicap over a lifetime.

+ 1 more reference

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Hereditary Spastic Paraplegia 3A:

Cerebral palsy MONDO:0006497

Overlapping Features Spastic diplegic cerebral palsy is the recurrent initial misdiagnosis of early-onset SPG3A, and the severe very-early-onset complex form with quadriplegia, dystonia and seizures mimics it closely. A family history, progression, or the absence of a perinatal insult should prompt genetic testing.

Show evidence (2 references)

PMID:39003427 SUPPORT Human Clinical

"Their ability to mimic CP also implies that genetic testing should be considered for patients with atypical forms of CP, given the implications for genetic counseling."

The authors' explicit recommendation that atypical cerebral palsy be genetically tested.

PMID:25193411 SUPPORT Human Clinical

"He manifested general hypertonia and hypokinesia since the neonatal period and was initially diagnosed with cerebral palsy."

A neonatal-onset case first labelled cerebral palsy.

Hereditary spastic paraplegia 4 (SPG4)

Overlapping Features The most common dominant HSP and the main alternative in a dominant family with pure spastic paraplegia. SPG3A has earlier onset, less frequent upper-limb hyperreflexia, less dorsal-column and sphincter involvement, and more lower-limb wasting and scoliosis; below age ten SPG3A is twice as frequent as SPG4.

Show evidence (2 references)

PMID:15596607 SUPPORT Human Clinical

"SPG3A patients had earlier symptom onset, less frequently increased reflexes in the upper limbs, decreased vibration sense in the lower limbs, and fewer sphincter disturbances, but more frequently observed wasting in the lower limbs and scoliosis."

The head-to-head clinical comparison with 126 SPG4 patients.

PMID:16401858 SUPPORT Human Clinical

"SPG3A was twice as frequent as SPG4 in patients with onset before age 10 years (31.8%)."

Onset before ten favours SPG3A over SPG4.

Hereditary sensory neuropathy type 1D (HSN1D) MONDO:0013381

Overlapping Features The allelic disorder: dominant ATL1 variants that present as a predominantly sensory axonal neuropathy with painless injuries rather than as spastic paraplegia. Reduced GTPase activity and a disrupted ER network are documented for the HSN1D allele and for many, though not all, SPG3A alleles; what determines whether sensory or motor long axons degenerate is unresolved. Curated in the separate Hereditary_Sensory_Neuropathy_Type_1D entry.

Show evidence (1 reference)

PMID:21194679 SUPPORT Human Clinical

"This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders."

Establishes HSN1D and SPG3A as allelic disorders.

Silver syndrome (SPG17) and other complicated HSPs with distal amyotrophy

Overlapping Features Spastic paraplegia with distal wasting of the hand muscles defines Silver syndrome, classically linked to BSCL2 at the SPG17 locus and clinically and genetically heterogeneous; the same phenotype has been reported with ATL1 and SPAST variants, so the complicated SPG3A subtype cannot be separated from SPG17 on clinical grounds.

Show evidence (2 references)

PMID:15372247 SUPPORT Human Clinical

"Silver syndrome (SS) is a complicated form of hereditary spastic paraplegia associated with distal wasting of the small muscles of the hands."

Defines the Silver syndrome phenotype that the complicated SPG3A subtype resembles.

PMID:19730024 SUPPORT Human Clinical

"These cases suggest that Silver syndrome may be associated with a wider variety of genotypes than previously described."

A Silver phenotype with an ATL1 variant, showing the clinical overlap.

🧫

Experimental Models

4

SPG3A patient iPSC-derived forebrain neurons (ATL1 p.Pro342Ser) IPSC_DERIVED_MODEL

Induced pluripotent stem cells from the skin fibroblasts of a girl with pure SPG3A carrying p.Pro342Ser, differentiated into forebrain neurons: the first human neuronal model of SPG3A.

Organism

human NCBITaxon:9606

Cell source

patient dermal fibroblast-derived iPSC

Publication

PMID:24908668

Pathograph links

Impaired Axonal ER Distribution, Organelle Transport and Axon Growth recapitulates fidelity: moderate Patient neurons show impaired axon growth and altered mitochondrial motility, and the growth defect is rescued by microtubule-binding agents.

Limitations: Immature cultured neurons with short axons cannot report the length-dependent degeneration of a metre-long corticospinal axon; a single patient line without an isogenic control.

Readouts

Axon growth

Direction: DECREASED

Interpretation: The axon-growth defect of SPG3A neurons.

Show evidence (1 reference)

PMID:24908668 SUPPORT In Vitro

"Axons of these SPG3A neurons showed impaired growth, recapitulating axonal defects in atlastin-1-depleted rat cortical neurons and impaired root hair growth in loss-of-function mutants of the ATL1 ortholog rhd3 in the plant Arabidopsis."

Reports the axon growth measurement.

Axon growth after microtubule-binding agents

Direction: RESTORED

Interpretation: Pharmacological rescue arm.

Show evidence (1 reference)

PMID:24908668 SUPPORT In Vitro

"The SPG3A axon growth defects could be rescued with microtubule-binding agents, emphasizing the importance of tubular ER interactions with the microtubule cytoskeleton in hereditary spastic paraplegia pathogenesis."

Reports the rescue measurement.

Show evidence (1 reference)

PMID:24908668 SUPPORT In Vitro

"We produced induced pluripotent stem cells from skin fibroblasts and differentiated these into forebrain neurons to generate a human neuronal model for SPG3A."

Describes the model as a human neuronal model for SPG3A.

Isogenic hPSC ATL1 A161P and patient P342S cortical projection neurons with astrocytes IPSC_DERIVED_MODEL

Isogenic human pluripotent stem cell lines carrying ATL1 A161P, and the P342S patient line, differentiated into cortical projection neurons and astrocytes, with neuron-astrocyte co-culture and conditioned-medium experiments.

Organism

human NCBITaxon:9606

Publication

PMID:33287888

Pathograph links

Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons recapitulates fidelity: moderate The model in which the astrocyte lipid-droplet and cholesterol-transfer defect was discovered and rescued.

Limitations: In vitro co-culture cannot show that glial cholesterol supply limits corticospinal axon survival in the patient brain; no in vivo confirmation exists.

Readouts

Astrocyte lipid droplet size

Direction: DECREASED

Interpretation: The glial lipid-droplet defect.

Show evidence (1 reference)

PMID:33287888 SUPPORT In Vitro

"Importantly, ATL1 mutations dysregulated proteolipid gene expression, reduced lipid droplet size in astrocytes, and unexpectedly disrupted cholesterol transfer from glia to neurons, leading to cholesterol deficiency in SPG3A cortical PNs."

Reports the lipid-droplet and cholesterol-transfer measurements.

Axonal transport and swellings after cholesterol or control-astrocyte medium

Direction: RESTORED

Interpretation: Rescue arm establishing the glial cholesterol deficit as causal for the neuronal phenotype.

Show evidence (1 reference)

PMID:33287888 SUPPORT In Vitro

"Applying cholesterol or conditioned medium from control astrocytes, a major source of cholesterol in the brain, rescued aberrant axonal transport and swellings in SPG3A cortical PNs."

Reports the rescue measurement.

Astrocyte lipid droplets, cholesterol efflux and neuronal axonal degeneration after GW3965

Direction: RESTORED

Interpretation: A second, pharmacological rescue arm acting on the astrocyte through LXR.

Show evidence (1 reference)

PMID:33287888 SUPPORT In Vitro

"Furthermore, treatment with the NR1H2 agonist GW3965 corrected lipid droplet defects in SPG3A astrocytes and promoted cholesterol efflux from astrocytes, leading to restoration of cholesterol levels and rescue of axonal degeneration in SPG3A cortical PNs."

Reports the LXR-agonist rescue measurements.

Show evidence (1 reference)

PMID:33287888 SUPPORT In Vitro

"We generated isogenic human pluripotent stem cell (hPSC) lines for two ATL1 missense mutations associated with SPG3A, the most common early-onset autosomal dominant HSP."

Describes the isogenic lines behind the model.

Impaired Axonal ER Distribution, Organelle Transport and Axon Growth recapitulates fidelity: moderate Reduced axonal outgrowth, impaired axonal transport and axonal swellings in cortical projection neurons.

Limitations: Cultured neurons cannot report length-dependent degeneration of a corticospinal axon in vivo.

Show evidence (1 reference)

PMID:33287888 SUPPORT In Vitro

"In hPSC-derived cortical PNs, ATL1 mutations resulted in reduced axonal outgrowth, impaired axonal transport, and accumulated axonal swellings, recapitulating disease-specific phenotypes."

The axonal phenotypes that make the model informative for the transport node.

SPG3A patient iPSC-derived cortical projection neurons (P342S and M408T) IPSC_DERIVED_MODEL

Cortical projection neurons differentiated from iPSCs of two SPG3A patients with distinct missense variants, profiled by RNA sequencing and calcium imaging and treated with the orally bioavailable LXR agonist LXR623.

Organism

human NCBITaxon:9606

Publication

PMID:41250225

Pathograph links

Presynaptic Dysfunction of Corticospinal Neurons recapitulates fidelity: moderate Synaptic gene and protein loss and reduced calcium activity in patient neurons from two variants, rescued by an LXR agonist.

Limitations: Cultured cortical neurons without their spinal targets; synaptic dysfunction and apoptosis in a dish may not correspond to the dying-back axonopathy without neuronal loss that characterises human HSP.

Readouts

Synaptic gene and protein expression

Direction: DECREASED

Interpretation: The synaptic dysfunction signature.

Show evidence (1 reference)

PMID:41250225 SUPPORT In Vitro

"We observed significant reductions of synaptic genes and proteins in cortical PNs from both SPG3A-P342S and SPG3A-M408T patient iPSCs, emphasizing synaptic dysfunction in SPG3A neurons."

Reports the synaptic measurements.

Synaptic proteins and calcium activity after LXR623

Direction: RESTORED

Interpretation: Pharmacological rescue arm through lipid metabolism.

Show evidence (1 reference)

PMID:41250225 SUPPORT In Vitro

"LXR623 significantly mitigated the reduction in synaptic proteins and calcium activity and rescued axonal degeneration and apoptosis in SPG3A cortical PNs."

Reports the rescue measurement.

Show evidence (1 reference)

PMID:41250225 SUPPORT In Vitro

"Here, by comparing SPG3A patient iPSC-derived neurons with control cells using RNA-sequencing, we identified synaptic dysfunction as a top-altered pathway in addition to lipid-related pathways."

The transcriptomic finding that makes the model informative for the synaptic node.

Autologous iPSC-derived lower motor neuron and myotube neuromuscular junction co-culture CO_CULTURE

Microfluidic co-cultures of lower motor neurons and myotubes differentiated from the same patient iPSC line, from three SPG3A and two SPG4 patients, used to model neuromuscular junction formation with the patient genotype in both cell types.

Organism

human NCBITaxon:9606

Culture

microfluidic compartmentalised neuron-muscle co-culture

Publication

PMID:36359747

Pathograph links

Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves partially recapitulates fidelity: low Patient lower motor neurons show axonal swellings and form fewer, less complex neuromuscular junctions, a correlate of the lower motor neuron arm of the complicated form.

Limitations: The SPG3A and SPG4 lines were pooled in the reported readouts, so no finding is uniquely SPG3A; an in vitro junction is not a degenerating peripheral nerve.

Readouts

Neuromuscular junction number and contact complexity

Direction: DECREASED

Interpretation: Impaired NMJ profile of HSP patient-derived motor neurons.

Show evidence (1 reference)

PMID:36359747 SUPPORT In Vitro

"Furthermore, NMJs from HSP-derived lines were lower in number and in contact point complexity, denoting an impaired NMJ profile"

Reports the NMJ measurement (pooled SPG3A and SPG4 lines).

Axonal swellings with acetylated alpha-tubulin accumulation in lower motor neurons

Direction: INCREASED

Interpretation: The axonal pathology hallmark reproduced in patient-derived lower motor neurons.

Show evidence (1 reference)

PMID:36359747 SUPPORT In Vitro

"Differentiation of the HSP-derived lines gave rise to lower MNs that could recapitulate pathological hallmarks, such as axonal swellings with accumulation of Acetyl-α-TUBULIN and reduction of SPASTIN levels."

Reports the axonal swelling measurement (pooled SPG3A and SPG4 lines).

Show evidence (1 reference)

PMID:36359747 SUPPORT In Vitro

"Three patients characterized by a mutation in the SPG3a gene, encoding the ATLASTIN GTPase 1 protein, and two patients with a mutation in the SPG4 gene, encoding the SPASTIN protein, were included in this study."

Establishes that SPG3A patient lines are among those modelled.

🐁

Animal Models

4

Atl1 K80A knock-in / Reep1 knockout double-mutant mouse

The first robust rodent HSP model. Atlastin-1 carries a K80A knock-in that abolishes GTPase activity and its binding partner Reep1 is knocked out; single mutants are mild, but the double mutant develops early-onset, rapidly progressive motor decline, and its corticospinal axons show a dosage-dependent transverse, periodic expansion of the ER into a ladder-like structure on FIB-SEM reconstruction, with fragmented axonal mitochondria and hypophosphorylated neurofilaments.

Species

Mus musculus

Genotype

Atl1 K80A/K80A knock-in (GTPase-dead) on a Reep1 -/- background

Genes

ATL1 hgnc:11231

Publication

PMID:35348668

Pathograph links

Disrupted Tubular ER Network in Neurons partially recapitulates fidelity: moderate The only in vivo observation of the ER of corticospinal axons under atlastin-1 GTPase loss; the ER is disorganised but expands rather than fragments.

Limitations: The lesion is a homozygous GTPase-dead knock-in combined with loss of Reep1, not a heterozygous patient missense allele, and the axonal ER expands rather than fragments; it is not known which change patient axons show.

Readouts

Transverse ER expansion in corticospinal axons (FIB-SEM)

Direction: INCREASED

Interpretation: Structural readout of the axonal ER lesion, dosage-dependent across the mutant genotypes.

Show evidence (1 reference)

PMID:35348668 SUPPORT Model Organism

"Also, ER in mutant corticospinal axons dramatically expands transversely and periodically in a mutation dosage-dependent manner to create a ladder-like appearance"

Reports the FIB-SEM measurement behind this readout.

Axonal mitochondrial fragmentation and neurofilament hypophosphorylation

Direction: INCREASED

Interpretation: Organelle and cytoskeletal changes that track the ER change, linking the ER lesion to the transport arm.

Show evidence (1 reference)

PMID:35348668 SUPPORT Model Organism

"In lockstep with changes in ER morphology, axonal mitochondria are fragmented and proportions of hypophosphorylated neurofilament H and M subunits are dramatically increased in Atl1KI/KI/Reep1-/- spinal cord."

Reports the mitochondrial and neurofilament measurements.

Show evidence (1 reference)

PMID:35348668 SUPPORT Model Organism

"Here, we have generated a robust, double mutant mouse model of HSP in which atlastin-1 is genetically modified with a K80A knock-in (KI) missense change that abolishes its GTPase activity, whereas its binding partner Reep1 is knocked out."

Describes the model whose corticospinal ER is informative for this node.

Progressive Lower-Limb Spasticity and Weakness partially recapitulates fidelity: moderate Early-onset, rapidly progressive motor decline on several tests, as a correlate of the human motor syndrome.

Limitations: Motor test decline in a mouse is not spasticity, and the course is rapid rather than the slow, near-static course of typical SPG3A.

Readouts

Motor function test performance

Direction: DECREASED

Interpretation: Behavioural correlate of the corticospinal lesion.

Show evidence (1 reference)

PMID:35348668 SUPPORT Model Organism

"Atl1KI/KI/Reep1-/- mice exhibit early onset and rapidly progressive declines in several motor function tests."

Reports the motor measurements behind this readout.

Drosophila atlastin loss-of-function models

The fly has a single atlastin orthologue, so loss of function is interpretable. Atlastin loss fragments the ER, and flies lacking atl or depleted of it in motor neurons show reduced larval crawling, progressive adult climbing decline, abnormally distributed axonal secretory organelles and depleted presynaptic terminals. Patient variants knocked into the endogenous gene reduce atlastin activity to different degrees and, when overexpressed over wild type, do not behave as dominant negatives. Flies carrying homologues of pure-HSP versus complex-HSP patient variants differ in severity and in cellular lesion: the pure-variant models accumulate lipid droplets in long motor nerves and respond partially to an LXR agonist, while the complex-variant models show neuronal ER disruption without a lipid phenotype and no LXR response. The null also shows age-dependent dopaminergic neuron death, which has no human counterpart.

Species

Drosophila melanogaster

Genotype

atl null (atl2), motor-neuron-specific atl RNAi, and CRISPR knock-in patient variants in endogenous atl

Publication

PMID:19633650

Pathograph links

Disrupted Tubular ER Network in Neurons recapitulates fidelity: moderate Loss of the fly atlastin fragments the ER, the defining cellular lesion.

Limitations: A null in an invertebrate with one atlastin; the human neuron expresses three paralogues, and the patient lesion is a heterozygous missense allele.

Show evidence (1 reference)

PMID:19633650 SUPPORT Model Organism

"Here we demonstrate that Drosophila Atlastin--the fly homologue of the mammalian GTPase atlastin 1 involved in hereditary spastic paraplegia--localizes on ER membranes and that its loss causes ER fragmentation."

The in vivo ER fragmentation on atlastin loss.

ATL1 Variant Impairing the Atlastin-1 GTPase Cycle perturbs fidelity: moderate Patient missense variants introduced into the endogenous fly gene test the functional consequence of each allele in vivo.

Limitations: Residues were transferred by alignment to the fly protein; the loss-of-function conclusion may not hold for human atlastin-1 in a three-paralogue background.

Show evidence (1 reference)

PMID:33177972 SUPPORT Model Organism

"Moreover, overexpression of the pathogenic variants in a wild type atlastin background does not give rise to the loss of function phenotypes expected for dominant negative mutations. These results indicate that the four pathological mutations investigated act through a loss of function mechanism."

The fly evidence for a loss-of-function rather than dominant-negative mechanism of four patient variants.

Presynaptic Dysfunction of Corticospinal Neurons partially recapitulates fidelity: low Motor-neuron atlastin loss depletes presynaptic terminals and disturbs synaptic vesicle pools, with progressive locomotor decline.

Limitations: Fly larval motor neurons are lower motor neurons at a neuromuscular junction, not corticospinal projection neurons, and the readout is locomotion rather than spasticity.

Readouts

Adult climbing ability

Direction: DECREASED

Interpretation: Progressive locomotor decline as the behavioural correlate of presynaptic failure.

Show evidence (1 reference)

PMID:28860117 SUPPORT Model Organism

"Using Drosophila, we demonstrate that downregulation or overexpression of Atlastin in motor neurons results in decreased crawling speed and contraction frequency in larvae, while adult flies show progressive decline in climbing ability."

Reports the locomotor measurements behind this readout.

Show evidence (1 reference)

PMID:28860117 SUPPORT Model Organism

"Additionally, axonal secretory organelles are abnormally distributed, whereas presynaptic proteins diminish at terminals and accumulate in distal axons, possibly in lysosomes."

The presynaptic depletion that makes the model informative for this node.

Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons partially recapitulates fidelity: low Flies carrying pure-HSP patient-variant homologues show disrupted lipid homeostasis in long motor nerves that is partially corrected by an LXR agonist, the same pharmacology that rescues the human stem-cell lipid phenotype.

Limitations: The fly lesion is lipid droplet accumulation within nerves, whereas the human astrocyte phenotype is smaller lipid droplets and failed cholesterol export; the direction differs and the fly has no astrocyte-to-neuron cholesterol shuttle of the human kind. The complex-variant flies show no lipid phenotype at all.

Readouts

Lipid droplet accumulation in motor nerves (pure-variant models)

Direction: INCREASED

Interpretation: Lipid homeostasis lesion in the pure-HSP fly models.

Show evidence (1 reference)

PMID:42419637 SUPPORT Model Organism

"Models of pure ATL1-HSP display disrupted lipid homeostasis, including lipid droplet accumulation within nerves comprising long motor neuron axons, which is partially ameliorated by treatment with a liver X receptor (LXR) agonist."

Reports the lipid droplet measurement and the LXR rescue arm.

Show evidence (1 reference)

PMID:42419637 SUPPORT Model Organism

"In contrast, complex ATL1-HSP Drosophila lack lipid droplet abnormalities and do not respond to LXR activation but instead show disruption of the neuronal endoplasmic reticulum, consistent with aberrant ER network regulation."

Bounds the link: only the pure-variant models carry the lipid lesion, so the model is informative for this node for pure SPG3A alleles only.

Show evidence (1 reference)

PMID:17030474 SUPPORT Model Organism

"As they aged, atl null flies were paralyzed by mechanical shock such as bumping or vortexing. Furthermore, the flies showed age-dependent degeneration of dopaminergic neurons."

The original atl null: a progressive, age-dependent neurological phenotype, but the dopaminergic neuron loss has no counterpart in SPG3A (see the model-mismatch discussion).

Zebrafish atl1 morphant

Morpholino knockdown of atl1 in the developing zebrafish severely reduces larval mobility, preceded by abnormal spinal motor axon architecture and a substantial up-regulation of BMP signalling; atlastin overexpression inhibits BMP signalling, and genetic or pharmacological BMP inhibition rescues the morphant.

Species

Danio rerio

Genotype

atl1 morpholino knockdown (and atl1 mRNA overexpression)

Publication

PMID:20935645

Pathograph links

Dysregulated BMP Signalling from Impaired BMPRII Trafficking partially recapitulates fidelity: moderate Establishes atlastin as a negative regulator of BMP signalling in vertebrate motor neurons and shows that BMP dysregulation is sufficient to disturb motor axon architecture.

Limitations: Knockdown raises BMP signalling, whereas patient dominant-negative variants blunt the BMP4 response in cells; the model is developmental, and zebrafish have no corticospinal tract.

Readouts

BMP pathway activity in atl1 morphants

Direction: INCREASED

Interpretation: Direction of BMP change on atlastin loss in vivo.

Show evidence (1 reference)

PMID:20935645 SUPPORT Model Organism

"Overexpression analyses confirmed that atlastin inhibits BMP signaling."

Reports the gain-of-function confirmation that atlastin inhibits BMP signalling.

Larval mobility after BMP inhibition

Direction: RESTORED

Interpretation: Rescue arm establishing causality of the BMP change for the motor phenotype.

Show evidence (1 reference)

PMID:20935645 SUPPORT Model Organism

"Finally, genetic or pharmacological inhibition of BMP signaling was sufficient to rescue the loss of mobility and spinal motor axon defects of atl1 morphants"

Reports the rescue measurement behind this readout.

Show evidence (1 reference)

PMID:20935645 SUPPORT Model Organism

"We found that knockdown of the gene for atlastin (atl1) caused a severe decrease in larval mobility that was preceded by abnormal architecture of spinal motor axons and was associated with a substantial upregulation of the bone morphogenetic protein (BMP) signaling pathway."

The morphant phenotype that makes the model informative for the BMP node.

C. elegans atln-1 mutant

In the PVD sensory neuron, atln-1 mutants with impaired GTPase activity lose the ER networks of the soma and dendrite branch points, ER tubules retract from higher-order dendrites, microtubules there are destabilised and mitochondrial fission at branch points fails; patient alleles reproduce the ER phenotype.

Species

Caenorhabditis elegans

Genotype

atln-1 GTPase-impaired mutants and knock-in of patient ATL1 alleles

Publication

PMID:30718476

Pathograph links

Disrupted Tubular ER Network in Neurons recapitulates fidelity: low In vivo neuronal ER morphology under atlastin loss, with patient alleles tested.

Limitations: A dendritic ER phenotype in an invertebrate sensory neuron; the human lesion is axonal, in a corticospinal projection neuron.

Readouts

ER network at soma and dendrite branch points

Direction: DECREASED

Interpretation: Loss of network ER, replaced by tubules, on GTPase impairment.

Show evidence (1 reference)

PMID:30718476 SUPPORT Model Organism

"In atln-1 mutants with impaired GTPase activity, ER networks in soma and dendrite branch points are reduced and replaced by tubules, and ER tubules retracted from high-order dendritic branches, causing destabilized microtubule in these branches."

Reports the ER morphology measurement behind this readout.

Show evidence (1 reference)

PMID:30718476 SUPPORT Model Organism

"Mutant alleles of Atlastin-1 found in Hereditary Spastic Paraplegia (HSP) patients show similar ER phenotypes, suggesting that neuronal ER impairment contributes to HSP disease pathogenesis."

Patient alleles reproduce the phenotype, which is what makes the worm informative for SPG3A.

{ }

Source YAML

click to show

name: Hereditary Spastic Paraplegia 3A
creation_date: "2026-09-12T18:30:00Z"
category: Mendelian
synonyms:
- SPG3A
- spastic paraplegia 3A
- ATL1-HSP
- ATL1 hereditary spastic paraplegia
- ATL1-related hereditary spastic paraplegia
- spastic paraplegia 3A, autosomal dominant
- autosomal dominant spastic paraplegia type 3
- FSP1
- Strumpell disease
description: >-
  Hereditary spastic paraplegia 3A (SPG3A, ATL1-HSP) is an autosomal dominant
  hereditary spastic paraplegia caused by heterozygous variants in ATL1, which
  encodes atlastin-1, a dynamin-like integral-membrane GTPase that catalyses
  homotypic fusion of endoplasmic reticulum tubules and is required for the
  interconnected tubular ER network. It is the second most common dominant HSP
  after SPG4 and the most common cause of HSP with onset before age ten. Most
  pathogenic variants are missense changes in the GTPase domain or the
  three-helix bundle. Many impair GTP hydrolysis-coupled membrane fusion and
  behave as dominant-negative alleles in cells, but at least two disease
  variants, including the one most frequently identified in patients, retain
  wild-type fusion activity in every assay, and several act as simple
  loss-of-function alleles
  in the fly, so no single molecular mechanism has been established for all
  alleles. In neurons the mutant protein disrupts the tubular ER, impairs axon
  growth and axonal transport, and, non-cell-autonomously, reduces astrocyte
  lipid-droplet formation and cholesterol supply to cortical projection
  neurons. The corticospinal axons that run from motor cortex to lumbosacral
  cord fail from their distal ends in a length-dependent pattern, producing the
  shared HSP syndrome of progressive lower-limb spasticity and weakness. SPG3A
  is distinguished among the dominant HSPs by an average onset of four years,
  a slow and often near-static course with preserved ambulation, and the
  relative infrequency of the dorsal-column and bladder involvement that is
  nearly universal in SPG4. Most cases are pure; about one in six mutation
  carriers in the largest screen had an axonal sensorimotor neuropathy with
  distal amyotrophy (the Silver syndrome
  phenotype), and a small mutational cluster, enriched for de novo variants,
  produces a severe very-early-onset complex phenotype that is often first
  diagnosed as cerebral palsy. Biallelic ATL1 variants in a few consanguineous
  families cause recessive disease with asymptomatic heterozygous parents.
  Heterozygous ATL1 variants also cause hereditary sensory neuropathy type 1D,
  an allelic disorder curated separately.
disease_term:
  preferred_term: hereditary spastic paraplegia 3A
  term:
    id: MONDO:0008437
    label: hereditary spastic paraplegia 3A
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008437
      label: hereditary spastic paraplegia 3A
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- Hereditary Spastic Paraplegia
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    ATL1-HSP is almost exclusively inherited in an autosomal dominant manner,
    and more than 95% of diagnosed individuals have an affected parent.
    Penetrance is incomplete: clinically unaffected carriers are recorded in
    several series, including one large French cohort in which five carriers
    were affected but asymptomatic and two had no clinical signs. De novo
    variants occur and are enriched among the severe complex presentations.
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ATL1-HSP is almost exclusively inherited in an autosomal dominant manner.
      More than 95% of individuals diagnosed with SPG3A have an affected parent
    explanation: GeneReviews statement of the mode of inheritance and the proportion of inherited cases.
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with ATL1-HSP has a 50% chance of inheriting
      the pathogenic variant.
    explanation: The transmission risk that follows from dominant inheritance, cited separately as a quantitative counselling claim.
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, several gene carriers were clinically affected but still
      asymptomatic (n = 5) or had no clinical signs (n = 2), indicating
      incomplete penetrance.
    explanation: Documents incomplete penetrance in the French SPG3A families.
  - reference: PMID:17502470
    reference_title: Hereditary spastic paraplegia 3A associated with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 12 probands (6.6%), we identified 12 different SPG3A mutations (11
      missense and 1 insertion/frameshift) of which 7 were novel and 3 were de
      novo.
    explanation: Records de novo variants and a further family with incomplete penetrance in a 182-family cohort.
  - reference: PMID:23483706
    reference_title: "Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By screening of additional HSP patients for the presence of these
      alterations, we identified three more cases and obtained additional
      evidence for reduced penetrance.
    explanation: Reduced penetrance confirmed at the c.1243/c.1244 hotspot in further patients.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    A rare recessive form is supported by a few consanguineous families in
    which affected members are homozygous for an ATL1 missense, splice-donor or
    frameshift variant while heterozygous relatives are asymptomatic.
    GeneReviews records two such families as the exception to dominant
    inheritance; further homozygous families have been reported since. This
    mode is curated as rare and emerging, not as coequal with dominant disease.
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Note: The exceptions are two families with biallelic ATL1 pathogenic
      variants.
    explanation: GeneReviews records the biallelic exception to the dominant pattern.
  - reference: PMID:24473461
    reference_title: Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing and segregation analysis revealed a homozygous
      novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six
      affected family members. Seven heterozygous carriers, five females and two
      males, showed no clinical signs of HSP with the exception of
      sub-clinically reduced vibration sensation in one adult female.
    explanation: The first consanguineous family with homozygous ATL1 disease and asymptomatic heterozygous carriers.
  - reference: PMID:37927245
    reference_title: "A novel homozygous variant in ATL1 associated with early onset spastic paraplegia 3A: Further evidence for autosomal recessive inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing reveals homozygosity for a novel likely pathogenic ATL1
      splice donor variant (c.522+1G>T) in an affected 5-year-old infant
      whereas the parents, heterozygous carriers, are asymptomatic.
    explanation: A third consanguineous family, here with a homozygous splice-donor variant.
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals carried novel ATL1 pathogenic variants (a de novo ATL1
      missense p.(Lys406Glu), a homozygous frameshift p.(Arg403Glufs*3) and a
      homozygous missense variant (p.Tyr367His)). The parents carrying the
      heterozygous frameshift and missense variants were asymptomatic.
    explanation: Two further homozygous cases, one frameshift and one missense, with asymptomatic heterozygous parents.
has_subtypes:
- name: Pure SPG3A
  display_name: Pure (uncomplicated) SPG3A
  description: >-
    The majority presentation: early-childhood-onset, slowly progressive,
    bilateral lower-limb spasticity and weakness without additional
    neurological features, and with dorsal-column sensory loss and bladder
    symptoms in only a minority.
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most persons with early-onset ATL1-HSP have a "pure" ("uncomplicated")
      HSP
    explanation: GeneReviews identifies the pure form as the usual presentation.
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical characteristic of these SPG3A patients was pure
      spasticity with very young onset of symptoms (mean age, 4.6 +/- 3.9 years)
      and slow progression.
    explanation: The French 34-patient series characterises the pure, early-onset, slowly progressive phenotype.
- name: Complicated SPG3A
  display_name: Complicated SPG3A with axonal neuropathy (Silver syndrome phenotype)
  description: >-
    About 17% of SPG3A mutation carriers in one 182-family screen had an
    axonal sensorimotor neuropathy with lower motor neuron involvement and
    distal amyotrophy, the Silver syndrome phenotype. No genotype predicts the neuropathy, and subclinical
    axonal polyneuropathy is found on electrophysiology in further cases.
  evidence:
  - reference: PMID:17502470
    reference_title: Hereditary spastic paraplegia 3A associated with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W)
      originating from 5 unrelated families presented with a complex form of
      hereditary spastic paraplegia associated with a neuropathy (17%). Our
      electrophysiological and pathological findings confirmed an axonal
      sensory-motor neuropathy.
    explanation: Quantifies the neuropathy-complicated fraction and characterises it as axonal sensorimotor.
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      complicated HSP with axonal motor neuropathy and/or distal amyotrophy with
      lower motor neuron involvement (Silver syndrome phenotype) has been
      observed.
    explanation: GeneReviews names the complicated Silver-syndrome-like presentation.
- name: Severe early-onset complex SPG3A
  display_name: Severe very-early-onset complex SPG3A (de novo mutational cluster or biallelic)
  description: >-
    A distinct phenotype, delineated across 537 published and novel cases, in
    which variants in a three-dimensional mutational cluster of atlastin-1
    (enriched for de novo variants, and also seen with some inherited ones)
    produce neurodevelopmental abnormalities, upper-limb spasticity, bulbar
    symptoms, peripheral neuropathy and brain-imaging abnormalities. The most
    severe cases begin in the first months of life with axial hypotonia
    followed by spastic quadriplegia, dystonia, seizures and intellectual
    disability, and are frequently first diagnosed as cerebral palsy. Biallelic
    ATL1 variants produce a similar severe early-onset picture.
  evidence:
  - reference: PMID:35925862
    reference_title: De novo variants cause complex symptoms in HSP-ATL1 (SPG3A) and uncover genotype-phenotype correlations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Establishing genotype-phenotype correlations, we find that symptoms that
      extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental
      abnormalities, upper limb spasticity, bulbar symptoms, peripheral
      neuropathy and brain imaging abnormalities) are prevalent in patients with
      variants located within this mutational cluster.
    explanation: Defines the complex phenotype and ties it to a structural mutational cluster in atlastin-1.
  - reference: PMID:35925862
    reference_title: De novo variants cause complex symptoms in HSP-ATL1 (SPG3A) and uncover genotype-phenotype correlations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we demonstrate that this distinct phenotypic signature is also prevalent
      in a subgroup of patients with inherited ATL1 variants and is largely
      explained by variant localization within a three-dimensional mutational
      cluster.
    explanation: The cluster, not de novo status itself, explains the phenotype, so inherited cluster variants belong to this subtype too.
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report three unrelated individuals presenting with very-early-onset
      (before 7 months) complex, and severe HSP phenotypes (axial hypotonia,
      spastic quadriplegia, dystonia, seizures and intellectual disability). For
      2 of the 3 patients, these phenotypes led to the initial diagnosis of
      cerebral palsy (CP).
    explanation: The three most severe reported cases, with the cerebral palsy misdiagnosis that characterises this subtype.
  - reference: PMID:25193411
    reference_title: Extremely severe complicated spastic paraplegia 3A with neonatal onset.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extremely severe complicated spastic paraplegia 3A can be caused by
      mutations in the linker or three-helix bundle of atlastin 1.
    explanation: An earlier neonatal-onset de novo case that localises the severe phenotype to the linker and three-helix bundle.
  - reference: PMID:42419637
    reference_title: Mutation-specific cellular mechanisms in Drosophila models of ATL1-associated hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Drosophila harbouring a complex ATL1-HSP mutation display reduced
      locomotor function, impaired development, and decreased survival relative
      to those carrying mutations associated with pure ATL1-HSP, recapitulating
      key aspects of clinical heterogeneity.
    explanation: >-
      Model-organism support that the pure versus complex split tracks the
      allele: the complex-variant homologue is more severe in the fly as well.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    No population prevalence has been measured for SPG3A itself. Autosomal
    dominant HSP as a whole has a pooled prevalence of 1.8 per 100,000 (range
    0.5 to 5.5), and SPG3A is the second most common dominant form in every
    population studied, accounting for about 5% of dominant HSP in a
    13,570-patient meta-analysis, 8 to 10% of familial dominant HSP on average
    across the literature, and 39% of young-onset dominant families once SPG4
    is excluded.
    Its share therefore places it well below 1 per 100,000, but the figure is
    derived rather than measured and is deliberately not recorded as a rate.
  evidence:
  - reference: PMID:24603320
    reference_title: "The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of autosomal dominant (AD) HSP (AD-HSP) ranged from 0.5 to
      5.5/10(5) and that of AR-HSP from 0.0 to 5.3/10(5), with pooled averages
      of 1.8/10(5) (95% CI: 1.0-2.7/10(5)) and 1.8/10(5) (95% CI:
      1.0-2.6/10(5)), respectively.
    explanation: The pooled prevalence of the dominant HSP group of which SPG3A is a fraction.
  - reference: PMID:24603320
    reference_title: "The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common AD-HSP form in every population was spastic paraplegia,
      autosomal dominant, type 4 (SPG4), followed by SPG3A
    explanation: Places SPG3A second among dominant HSPs across populations.
  - reference: PMID:31745725
    reference_title: "Genotype-phenotype associations in hereditary spastic paraplegia: a systematic review and meta-analysis on 13,570 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of mutations in SPAST (25%) was higher than REEP1 (3%), as
      well as ATL1 (5%) in AD-HSP patients.
    explanation: The pooled ATL1 share of dominant HSP across 147 studies.
  - reference: PMID:31594988
    reference_title: Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although its contribution is much less than that of SPG4, on average it
      accounts for 2–3% of total HSP cases and 8–10% of family AD HSP cases
    explanation: The literature-average share of all HSP and of familial dominant HSP, quoted from the paper's introduction.
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    Typical SPG3A is mild to moderate: progression is slow, wheelchair
    dependence is relatively rare, and early-onset HSP in general keeps
    independent walking longer than later-onset disease. But because onset is
    so early the cumulative disease duration is long and the eventual handicap
    can exceed that of other dominant HSPs, and the severe very-early-onset
    complex subtype rarely achieves independent ambulation.
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The rate of progression in ATL1-HSP is slow, and wheelchair dependency or
      need for a walking aid (cane, walker, or wheelchair) is relatively rare.
    explanation: GeneReviews on the slow course and preserved ambulation of typical SPG3A.
  - reference: PMID:26856398
    reference_title: "Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early onset cases were able to maintain free walking significantly longer
      and were at less risk to become wheelchair dependent.
    explanation: In the 608-patient German cohort early onset, the SPG3A hallmark, predicts a milder course.
  - reference: PMID:16401858
    reference_title: SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype was pure HSP, but disease duration was longer than in
      non-SPG3A/SPG4 patients, leading ultimately to greater handicap.
    explanation: >-
      The counterweight: long disease duration from early onset accumulates handicap over a lifetime.
  - reference: PMID:34782662
    reference_title: Clinical and molecular characterization of a large cohort of childhood onset hereditary spastic paraplegias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survival curves to major handicap and cross-sectional Spastic Paraplegia
      Rating Scale progressions confirmed the slow neurological deterioration in
      SPG4 and SPG3A.
    explanation: A childhood-onset Brazilian cohort confirming slow deterioration in SPG3A.
mechanistic_hypotheses:
- hypothesis_group_id: er_fusion_deficit
  hypothesis_label: Impaired atlastin-1 ER tubule fusion disrupts the axonal ER network
  status: CANONICAL
  description: >-
    Disease variants reduce GTP hydrolysis-coupled homotypic fusion of ER
    tubules, the tubular ER fails to form three-way junctions and to extend
    along the axon, and the long corticospinal axon loses the membrane, lipid
    and calcium-handling functions of a continuous ER. This is the model that
    the atlastin structural and reconstitution work, the atlastin-null fly and
    worm, the triple-knockout cell lines and the K80A knock-in mouse all
    support.
  evidence:
  - reference: PMID:21368113
    reference_title: Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, our results show that mutations in ATL1 causing hereditary
      spastic paraplegia compromise homotypic ER fusion.
    explanation: Structural and fusion-assay demonstration that disease variants compromise the fusion reaction.
  - reference: PMID:25761634
    reference_title: ER network formation and membrane fusion by atlastin1/SPG3A disease variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Taken together, these findings indicate that a deficit in the membrane
      fusion activity of atlastin1 may be a key contributor, but is not
      required, for HSP causation.
    explanation: >-
      Cited on the canonical hypothesis because it both supports a fusion
      deficit as a key contributor and bounds the claim: fusion loss is not
      required for disease.
- hypothesis_group_id: fusion_independent_variant_effects
  hypothesis_label: Fusion-independent functions of atlastin-1 (BMP receptor trafficking, calcium entry) contribute to axonopathy
  status: ALTERNATIVE
  description: >-
    At least two disease variants, including the most frequently identified
    one, retain wild-type ER network formation, GTPase, dimerisation and fusion
    activity, so a fusion deficit cannot be the whole explanation. Candidate
    fusion-independent mechanisms are dominant-negative disruption of BMPRII
    trafficking with dysregulated BMP signalling, which in zebrafish controls
    motor axon architecture, and reduced store-operated calcium entry.
  evidence:
  - reference: PMID:25761634
    reference_title: ER network formation and membrane fusion by atlastin1/SPG3A disease variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly however, at least two disease variants, one of which
      represents that most frequently identified in SPG3A HSP patients,
      displayed wild-type levels of activity in all assays.
    explanation: The observation that motivates a fusion-independent mechanism.
  - reference: PMID:23079343
    reference_title: Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our results suggest that HSP-causing atlastin-1 mutations exhibit a
      dominant-negative effect on trafficking of BMPRII, which disrupts the BMP
      pathway in neurons.
    explanation: A fusion-independent, dominant-negative effect of disease variants on BMP receptor trafficking.
  - reference: PMID:28240257
    reference_title: Atlastin regulates store-operated calcium entry for nerve growth factor-induced neurite outgrowth.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results suggest that SOCE plays an important role in neuronal
      regeneration, and mutations in ATL1 may cause HSP, partly by undermining
      SOCE.
    explanation: Store-operated calcium entry as a further candidate route from mutant atlastin-1 to neurite growth failure.
- hypothesis_group_id: glial_cholesterol_supply
  hypothesis_label: Non-cell-autonomous astrocyte cholesterol deficit drives cortical projection neuron degeneration
  status: EMERGING
  description: >-
    Isogenic and patient-derived human pluripotent stem cell models show that
    ATL1 variants reduce astrocyte lipid-droplet size and cholesterol transfer
    to neurons, leaving cortical projection neurons cholesterol-deficient, and
    that cholesterol, control astrocyte medium or LXR agonists rescue axonal
    transport, swellings and degeneration. The lipid-droplet link follows from
    atlastin's conserved role in ER fusion, but the human in vivo relevance is
    untested.
  evidence:
  - reference: PMID:33287888
    reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results reveal a non-cell autonomous mechanism underlying axonal
      degeneration of cortical PNs mediated by impaired cholesterol homeostasis
      in glia.
    explanation: The stem-cell study that proposes the glial cholesterol mechanism.
  - reference: PMID:41250225
    reference_title: LXR agonist rescues synaptic dysfunction and degeneration in SPG3A patient-specific iPSC-derived neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      LXR623 significantly mitigated the reduction in synaptic proteins and
      calcium activity and rescued axonal degeneration and apoptosis in SPG3A
      cortical PNs.
    explanation: Pharmacological rescue through an LXR agonist that modulates lipid metabolism and transfer.
  - reference: PMID:42419637
    reference_title: Mutation-specific cellular mechanisms in Drosophila models of ATL1-associated hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Models of pure ATL1-HSP display disrupted lipid homeostasis, including
      lipid droplet accumulation within nerves comprising long motor neuron
      axons, which is partially ameliorated by treatment with a liver X
      receptor (LXR) agonist.
    explanation: >-
      In vivo support for a lipid lesion that answers to LXR agonism, in flies
      carrying pure-HSP patient variants; the lesion is in nerve rather than
      glia and runs in the opposite direction to the astrocyte droplet
      phenotype.
pathophysiology:
- name: ATL1 Variant Impairing the Atlastin-1 GTPase Cycle
  conforms_to: "corticospinal_tract_axonopathy#Long-Axon Maintenance Machinery Defect"
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Atlastin-1 is a neuronally enriched, dynamin-like integral-membrane GTPase
    of the tubular ER, built from an N-terminal GTPase domain, a three-helix
    bundle, two transmembrane segments and a C-terminal amphipathic tail.
    GTP-dependent head-to-head dimerisation across apposed membranes, crossover
    of the three-helix bundles and GTP hydrolysis pull the membranes together.
    Heterozygous ATL1 missense variants cluster in the GTPase domain and the
    three-helix bundle and disturb this cycle in allele-specific ways: several
    reduce GTP hydrolysis and dimerisation, one (F151S) uncouples the catalytic
    site from nucleotide loading, and others destabilise the GTP-bound
    crossover dimer or the membrane-embedded helix. Mutant protein forms mixed
    oligomers with wild-type atlastin-1 and in cells acts in a dominant-negative
    manner, although in the fly several patient variants behave as plain
    loss-of-function alleles and biallelic variants cause recessive disease, so
    the dominant-negative label is recorded here as the best-supported, not
    the only, mechanism.
  genetic_context:
    gene:
      preferred_term: ATL1
      term:
        id: hgnc:11231
        label: ATL1
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    notes: >-
      Dominant-negative is the category with the most direct human-variant
      evidence (mixed oligomer formation, dominant-negative disruption of ER
      reticularisation and BMPRII trafficking in cells). Loss of function is
      supported by CRISPR knock-in flies and by the recessive families, and at
      least two frequent variants have no measurable functional deficit. See
      the dominant-negative versus loss-of-function discussion.
  cell_types:
  - preferred_term: corticospinal upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  molecular_functions:
  - preferred_term: atlastin-1 GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: endoplasmic reticulum organization (ER-shaping machinery)
    term:
      id: GO:0007029
      label: endoplasmic reticulum organization
    modifier: DYSREGULATED
  cellular_components:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  evidence:
  - reference: PMID:11685207
    reference_title: Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report the identification of mutations in a newly identified
      GTPase gene, SPG3A, in ADHSP affected individuals.
    explanation: The gene discovery establishing that SPG3A is caused by mutations in the atlastin-1 GTPase.
  - reference: PMID:16537571
    reference_title: SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we demonstrate that several missense SPG3A mutant atlastin-1
      proteins have impaired GTPase activity and thus may act in a
      dominant-negative, loss-of-function manner by forming mixed oligomers with
      wild-type atlastin-1.
    explanation: Shows impaired GTPase activity of patient variants and the mixed-oligomer basis for a dominant-negative effect.
  - reference: PMID:21220294
    reference_title: Structural basis for the nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mechanism is affected in several mutants associated with HSP,
      providing insights into disease pathogenesis.
    explanation: The atlastin-1 crystal structures show that disease variants perturb nucleotide-dependent dimerisation.
  - reference: PMID:29180453
    reference_title: A hereditary spastic paraplegia-associated atlastin variant exhibits defective allosteric coupling in the catalytic core.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we elucidate structural and functional defects of an atypical
      hereditary spastic paraplegia mutant, ATL1-F151S, that is impaired in its
      nucleotide-hydrolysis cycle but can still adopt a high-affinity homodimer
      when bound to a transition-state analog.
    explanation: >-
      An allele-specific defect: F151S breaks allosteric coupling between the active site and nucleotide loading.
  - reference: PMID:38509071
    reference_title: Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, we found that two disease-causing mutations affect human ATL1
      activity by destabilizing GTP binding-induced loose crossover dimer
      formation and the membrane-embedded helix, respectively.
    explanation: Single-molecule FRET shows two further allele-specific ways of breaking the GTPase cycle.
  - reference: PMID:25761634
    reference_title: ER network formation and membrane fusion by atlastin1/SPG3A disease variants.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly however, at least two disease variants, one of which
      represents that most frequently identified in SPG3A HSP patients,
      displayed wild-type levels of activity in all assays.
    explanation: >-
      Refutes the universality of this node's claim: the most frequently
      identified variant has no measurable GTPase, dimerisation, ER-network or
      fusion deficit, so impairment of the GTPase cycle cannot explain every
      allele.
  - reference: PMID:33177972
    reference_title: In vivo Analysis of CRISPR/Cas9 Induced Atlastin Pathological Mutations in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that all pathological mutations examined reduce atlastin
      activity in vivo although to different degrees of severity.
    explanation: Four patient variants introduced into the endogenous fly gene all reduce atlastin activity in vivo.
  downstream:
  - target: Impaired Homotypic ER Tubule Fusion
    causal_link_type: DIRECT
    hypothesis_groups:
    - er_fusion_deficit
    description: >-
      The GTPase cycle is what drives fusion, so an allele that blocks GTP
      hydrolysis or crossover dimerisation cannot support the fusion reaction.
    evidence:
    - reference: PMID:19633650
      reference_title: Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In contrast, GTPase-deficient Atlastin is inactive, unable to form
        trans-oligomeric complexes owing to failure to self-associate, and
        incapable of promoting fusion in vitro.
      explanation: GTPase-deficient atlastin cannot tether or fuse membranes, which is the edge from a GTPase-cycle defect to fusion failure.
    - reference: PMID:21368113
      reference_title: Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Finally, our results show that mutations in ATL1 causing hereditary
        spastic paraplegia compromise homotypic ER fusion.
      explanation: Direct demonstration in fusion assays that the disease variants compromise homotypic ER fusion.
  - target: Dysregulated BMP Signalling from Impaired BMPRII Trafficking
    causal_link_type: DIRECT
    hypothesis_groups:
    - fusion_independent_variant_effects
    description: >-
      Mutant atlastin-1 binds BMPRII and, in a dominant-negative manner, blocks
      its trafficking to the cell surface; this does not require loss of fusion
      activity.
    evidence:
    - reference: PMID:23079343
      reference_title: Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Endogenous and expressed atlastin-1 showed a strong interaction with BMP
        receptors II (BMPRII) and analyzed missense, HSP-causing mutations R239C
        and R495W disrupted BMPRII trafficking to the cell surface.
      explanation: Two patient variants disrupt BMPRII surface trafficking, linking the mutant protein directly to the BMP arm.
- name: Impaired Homotypic ER Tubule Fusion
  biological_scale: MOLECULAR
  description: >-
    Atlastin-1 drives GTP-dependent homotypic fusion of ER tubules: GTP binding
    reorients the GTPase domain against the three-helix bundle to permit
    self-association across membranes, and hydrolysis completes the fusion.
    Human atlastin-1 catalyses lipid mixing directly once its C-terminal
    autoinhibition is relieved. SPG3A variants that break any step of this
    cycle leave apposed tubules tethered but unfused, so the three-way junctions
    that make the tubular ER a continuous network fail to form.
  biological_processes:
  - preferred_term: homotypic endoplasmic reticulum membrane fusion
    term:
      id: GO:0016320
      label: endoplasmic reticulum membrane fusion
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  evidence:
  - reference: PMID:19633650
    reference_title: Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro experiments confirm that Atlastin autonomously drives membrane
      fusion in a GTP-dependent fashion.
    explanation: Establishes atlastin as the autonomous, GTP-dependent ER fusogen.
  - reference: PMID:21930898
    reference_title: GTP-dependent packing of a three-helix bundle is required for atlastin-mediated fusion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      GTP binding induces a conformational change that reorients the GTPase
      domain relative to the 3HB to permit self-association, but the ability to
      hydrolyze GTP is required for full fusion, indicating that nucleotide
      binding and hydrolysis play distinct roles.
    explanation: The mechanistic sequence, binding then hydrolysis, that disease variants interrupt at different steps.
  - reference: PMID:34817557
    reference_title: Reconstitution of human atlastin fusion activity reveals autoinhibition by the C terminus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we report successful reconstitution of fusion activity by the human
      ATLs. Unexpectedly, the major splice isoforms of ATL1 and ATL2 are each
      autoinhibited, albeit to differing degrees.
    explanation: Shows that human atlastin-1 itself, not only the fly orthologue, catalyses fusion, so the human step is real.
  downstream:
  - target: Disrupted Tubular ER Network in Neurons
    causal_link_type: DIRECT
    hypothesis_groups:
    - er_fusion_deficit
    description: >-
      Interconnection of ER tubules into a polygonal network depends on
      atlastin-mediated fusion, so fusion failure leaves long unbranched
      tubules with few three-way junctions.
    evidence:
    - reference: PMID:19665976
      reference_title: "A class of dynamin-like GTPases involved in the generation of the tubular ER network."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we show that mammalian atlastins, which are dynamin-like, integral
        membrane GTPases, interact with the tubule-shaping proteins. The
        atlastins localize to the tubular ER and are required for proper network
        formation in vivo and in vitro.
      explanation: Atlastins are required for network formation, so their loss of fusion activity disrupts the network.
    - reference: PMID:18270207
      reference_title: Atlastin GTPases are required for Golgi apparatus and ER morphogenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Interestingly, expression of SPG3A mutant or dominant-negative atlastin
        proteins lacking GTPase activity causes prominent inhibition of ER
        reticularization, suggesting a role for atlastin GTPases in the
        formation of three-way junctions in the ER.
      explanation: SPG3A mutant protein itself inhibits ER reticularisation in cells.
  - target: Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - glial_cholesterol_supply
    description: >-
      Atlastin-mediated ER fusion sets lipid-droplet size in worm, fly and
      mammalian cells, and the effect scales with fusion activity; in human
      ATL1-mutant astrocytes lipid droplets are small and cholesterol export to
      neurons fails.
    evidence:
    - reference: PMID:23684613
      reference_title: A conserved role for atlastin GTPases in regulating lipid droplet size.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The effect of atlastin-1 on LD size correlates with its activity to
        promote membrane fusion in vitro.
      explanation: Ties lipid-droplet size directly to atlastin-1 fusion activity, the edge from fusion loss to the lipid arm.
- name: Disrupted Tubular ER Network in Neurons
  biological_scale: CELLULAR
  description: >-
    Without atlastin-1-mediated fusion the peripheral ER of the neuron becomes
    long, unbranched and poorly interconnected: three-way junctions are lost,
    the network retracts from distal neurites, and ER-microtubule coordination
    through the atlastin-1, spastin and REEP1 complex is disturbed. In the
    corticospinal axons of the Atl1 K80A knock-in, Reep1-null mouse the axonal
    ER instead expands transversely into a periodic ladder-like structure,
    dosage-dependently, with fragmented mitochondria and hypophosphorylated
    neurofilaments in lockstep. Whether the ER of patient corticospinal axons
    shows either change is not known.
  cell_types:
  - preferred_term: corticospinal upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  cellular_components:
  - preferred_term: endoplasmic reticulum tubular network
    term:
      id: GO:0071782
      label: endoplasmic reticulum tubular network
  biological_processes:
  - preferred_term: endoplasmic reticulum tubular network organization
    term:
      id: GO:0071786
      label: endoplasmic reticulum tubular network organization
    modifier: DECREASED
  evidence:
  - reference: PMID:19665976
    reference_title: "A class of dynamin-like GTPases involved in the generation of the tubular ER network."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Since atlastin-1 mutations cause a common form of hereditary spastic
      paraplegia, we suggest ER-shaping defects as a neuropathogenic mechanism.
    explanation: Proposes the ER-shaping defect as the neuropathogenic mechanism of SPG3A.
  - reference: PMID:20200447
    reference_title: "Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The atlastin-1 GTPase interacts with spastin, a microtubule-severing
      ATPase, as well as with the DP1/Yop1p and reticulon families of ER-shaping
      proteins, and SPG3A caused by atlastin-1 mutations has been linked
      pathogenically to abnormal ER morphology.
    explanation: Places atlastin-1 in the spastin and REEP1 ER-shaping complex and links SPG3A to abnormal ER morphology.
  - reference: PMID:27669642
    reference_title: Mammalian knock out cells reveal prominent roles for atlastin GTPases in ER network morphology.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ER morphology is markedly disrupted in these triple KO cells, with
      prominent impairment in formation of three-way ER tubule junctions.
    explanation: Mammalian cells lacking all three atlastins lose three-way junctions, the specific network defect of atlastin loss.
  - reference: PMID:30718476
    reference_title: Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mutant alleles of Atlastin-1 found in Hereditary Spastic Paraplegia (HSP)
      patients show similar ER phenotypes, suggesting that neuronal ER
      impairment contributes to HSP disease pathogenesis.
    explanation: Patient alleles reproduce the neuronal ER-network defect of the worm atlastin mutant in vivo.
  - reference: PMID:35348668
    reference_title: Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Also, ER in mutant corticospinal axons dramatically expands transversely
      and periodically in a mutation dosage-dependent manner to create a
      ladder-like appearance
    explanation: The only in vivo view of corticospinal axonal ER under atlastin-1 GTPase loss, from the double-mutant mouse.
  downstream:
  - target: Impaired Axonal ER Distribution, Organelle Transport and Axon Growth
    causal_link_type: DIRECT
    hypothesis_groups:
    - er_fusion_deficit
    description: >-
      A fragmented ER cannot be carried into and along the growing axon, and
      its coupling to microtubules and mitochondria is lost, which is why
      microtubule-binding agents rescue the axon-growth defect of SPG3A
      neurons.
    evidence:
    - reference: PMID:24908668
      reference_title: Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The SPG3A axon growth defects could be rescued with microtubule-binding
        agents, emphasizing the importance of tubular ER interactions with the
        microtubule cytoskeleton in hereditary spastic paraplegia pathogenesis.
      explanation: Rescue by microtubule-binding agents ties the ER-network defect to the axon-growth failure through ER-microtubule interaction.
    - reference: PMID:27605706
      reference_title: "Spastin, atlastin, and ER relocalization are involved in axon but not dendrite regeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In atlastin RNAi and spastin mutant animals, ER accumulation near single
        growing axon tips was impaired.
      explanation: Loss of atlastin prevents the ER from concentrating at the growing axon tip, the distribution step this edge claims.
  - target: Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In the complicated form the same ER-network lesion is presumed to injure
      the long peripheral motor and sensory axons, as it does in the allelic
      disorder HSN1D, but the intermediate steps have not been shown in SPG3A.
- name: Dysregulated BMP Signalling from Impaired BMPRII Trafficking
  biological_scale: CELLULAR
  description: >-
    Atlastin-1 binds the type II BMP receptor and inhibits BMP signalling, in
    concert with the other HSP proteins spastin, NIPA1 and spartin. Patient
    variants R239C and R495W block BMPRII trafficking to the cell surface in a
    dominant-negative manner and blunt Smad1/5 phosphorylation after BMP4,
    whereas knockdown of atlastin in zebrafish substantially up-regulates BMP
    signalling and disorganises spinal motor axons. The direction of the change
    therefore differs between the human dominant-negative variants and
    loss-of-function models, which is why the process is recorded as
    dysregulated rather than increased or decreased.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:23079343
    reference_title: Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Expression of mutant forms of atlastin-1 also interfered with the
      signaling response to BMP4 stimulation and reduced phosphorylation of Smad
      1/5 proteins.
    explanation: Patient variants blunt the BMP4 signalling response in cells.
  - reference: PMID:20935645
    reference_title: Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that knockdown of the gene for atlastin (atl1) caused a severe
      decrease in larval mobility that was preceded by abnormal architecture of
      spinal motor axons and was associated with a substantial upregulation of
      the bone morphogenetic protein (BMP) signaling pathway.
    explanation: Atlastin loss in zebrafish up-regulates BMP signalling, the opposite direction from the cell data, hence the dysregulated modifier.
  - reference: PMID:30082270
    reference_title: BMP- and neuropilin 1-mediated motor axon navigation relies on spastin alternative translation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We next showed that M1 spastin, together with HSP proteins atlastin 1 and
      NIPA1, drives motor axon targeting by repressing BMP signalling
    explanation: Places atlastin-1 in a shared HSP-protein module that represses BMP signalling in vertebrate motor axons.
  downstream:
  - target: Impaired Axonal ER Distribution, Organelle Transport and Axon Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - fusion_independent_variant_effects
    description: >-
      BMP signalling tunes motor axon architecture; in atlastin-depleted
      zebrafish, inhibiting BMP signalling is sufficient to rescue the motor
      axon defects, so the BMP arm feeds into the axonal phenotype.
    evidence:
    - reference: PMID:20935645
      reference_title: Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Finally, genetic or pharmacological inhibition of BMP signaling was
        sufficient to rescue the loss of mobility and spinal motor axon defects
        of atl1 morphants
      explanation: Rescue by BMP inhibition shows the BMP arm is causal for the axonal phenotype in this model.
- name: Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons
  biological_scale: CELLULAR
  description: >-
    ATL1 variants in human pluripotent stem cell-derived astrocytes dysregulate
    proteolipid gene expression, shrink lipid droplets and disrupt cholesterol
    transfer to neurons, leaving co-cultured cortical projection neurons
    cholesterol-deficient. This is a non-cell-autonomous arm: the neuronal
    axonal defects are rescued by exogenous cholesterol, by conditioned medium
    from control astrocytes, or by liver-X-receptor agonists that restore
    astrocyte cholesterol efflux.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: cholesterol transport from astrocytes to neurons
    term:
      id: GO:0030301
      label: cholesterol transport
    modifier: DECREASED
  evidence:
  - reference: PMID:33287888
    reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, ATL1 mutations dysregulated proteolipid gene expression,
      reduced lipid droplet size in astrocytes, and unexpectedly disrupted
      cholesterol transfer from glia to neurons, leading to cholesterol
      deficiency in SPG3A cortical PNs.
    explanation: The core observation of the astrocyte lipid-droplet and cholesterol-transfer defect in human ATL1-mutant cells.
  - reference: PMID:23684613
    reference_title: A conserved role for atlastin GTPases in regulating lipid droplet size.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using genetic screens in C. elegans for LD morphology defects in
      intestinal cells, we found that mutations in atlastin, a GTPase required
      for homotypic fusion of endoplasmic reticulum (ER) membranes, cause not
      only ER morphology defects, but also a reduction in LD size.
    explanation: The conserved atlastin lipid-droplet function from which the astrocyte defect follows.
  downstream:
  - target: Impaired Axonal ER Distribution, Organelle Transport and Axon Growth
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - glial_cholesterol_supply
    description: >-
      Cholesterol deficiency in the projection neuron impairs axonal transport
      and produces swellings; restoring cholesterol, from any source, rescues
      them.
    evidence:
    - reference: PMID:33287888
      reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Applying cholesterol or conditioned medium from control astrocytes, a
        major source of cholesterol in the brain, rescued aberrant axonal
        transport and swellings in SPG3A cortical PNs.
      explanation: Rescue by cholesterol establishes the glial cholesterol deficit as causal for the neuronal axonal transport defect.
- name: Impaired Axonal ER Distribution, Organelle Transport and Axon Growth
  conforms_to: "corticospinal_tract_axonopathy#Impaired Axonal Transport and Organelle Distribution"
  biological_scale: CELLULAR
  description: >-
    Atlastin-1 is enriched in growth cones, axonal varicosities and branch
    points of cortical neurons, and its knockdown or mutation reduces axon
    formation and elongation. Human SPG3A neurons show impaired axon growth,
    altered mitochondrial motility, impaired axonal transport and axonal
    swellings, and dominant-negative ATL1 blocks NGF-driven neurite outgrowth
    in PC-12 cells partly by undermining store-operated calcium entry. In the
    double-mutant mouse, axonal mitochondria fragment and neurofilament H and M
    become hypophosphorylated in lockstep with the ER change. Because SPG3A
    begins so early, a developmental component to the axonopathy has been
    proposed alongside failure of maintenance.
  cell_types:
  - preferred_term: corticospinal upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  biological_processes:
  - preferred_term: axon extension
    term:
      id: GO:0048675
      label: axon extension
    modifier: DECREASED
  - preferred_term: axonal transport
    term:
      id: GO:0098930
      label: axonal transport
    modifier: DECREASED
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:16537571
    reference_title: SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Indeed, knock-down of atlastin-1 expression in these neurons using small
      hairpin RNAs reduces the number of neuronal processes and impairs axon
      formation and elongation during development.
    explanation: Atlastin-1 loss impairs axon formation and elongation in cortical neurons.
  - reference: PMID:24908668
    reference_title: Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Axons of these SPG3A neurons showed impaired growth, recapitulating axonal
      defects in atlastin-1-depleted rat cortical neurons and impaired root hair
      growth in loss-of-function mutants of the ATL1 ortholog rhd3 in the plant
      Arabidopsis.
    explanation: Patient iPSC-derived neurons reproduce the axon-growth defect.
  - reference: PMID:24908668
    reference_title: Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SPG3A neurons showed alterations in mitochondrial motility.
    explanation: Mitochondrial motility is altered in the same neurons, the organelle-distribution part of this node.
  - reference: PMID:33287888
    reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In hPSC-derived cortical PNs, ATL1 mutations resulted in reduced axonal
      outgrowth, impaired axonal transport, and accumulated axonal swellings,
      recapitulating disease-specific phenotypes.
    explanation: Isogenic and patient cortical projection neurons show reduced outgrowth, impaired transport and swellings.
  - reference: PMID:28240257
    reference_title: Atlastin regulates store-operated calcium entry for nerve growth factor-induced neurite outgrowth.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that dominant-negative mutants of ATL1 in PC-12 cells
      inhibit nerve growth factor (NGF)-induced neurite outgrowth.
    explanation: Dominant-negative ATL1 blocks neurite outgrowth, with reduced store-operated calcium entry as the proposed intermediate.
  - reference: PMID:35348668
    reference_title: Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In lockstep with changes in ER morphology, axonal mitochondria are
      fragmented and proportions of hypophosphorylated neurofilament H and M
      subunits are dramatically increased in Atl1KI/KI/Reep1-/- spinal cord.
    explanation: In vivo, the ER change is accompanied by mitochondrial fragmentation and cytoskeletal change in corticospinal axons.
  - reference: PMID:23999326
    reference_title: Atlastin-1 regulates dendritic morphogenesis in mouse cerebral cortex.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with this, in vivo expression of wild type ATL1, but not of
      the mutant R217Q, increased dendritic growth of the cortical neurons.
    explanation: >-
      In the mouse cortex in vivo, the GTPase-dead patient variant R217Q cannot
      support the neurite growth that wild-type atlastin-1 drives, extending
      the growth defect from axons in culture to dendrites in a living cortex.
  downstream:
  - target: Presynaptic Dysfunction of Corticospinal Neurons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failure to deliver secretory organelles and presynaptic components along
      the axon depletes the terminal, as shown for fly motor neurons.
    evidence:
    - reference: PMID:28860117
      reference_title: Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Additionally, axonal secretory organelles are abnormally distributed,
        whereas presynaptic proteins diminish at terminals and accumulate in
        distal axons, possibly in lysosomes.
      explanation: The trafficking defect leaves presynaptic proteins stranded in the distal axon rather than at the terminal.
  - target: Distal Length-Dependent Corticospinal Axon Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic failure of organelle and membrane supply is the proposed route to
      distal degeneration of the longest axons; the terminal injury pathway in
      human corticospinal axons is inferred rather than observed.
    evidence:
    - reference: PMID:18270207
      reference_title: Atlastin GTPases are required for Golgi apparatus and ER morphogenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Abnormal morphogenesis of the ER and Golgi resulting from mutations in
        atlastin-1 may ultimately underlie SPG3A by interfering with proper
        membrane distribution or polarity of the long corticospinal motor
        neurons.
      explanation: The proposed mechanism by which the organelle-distribution defect produces the length-dependent axonopathy.
  - target: Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Patient iPSC-derived lower motor neurons carry the same axonal swellings
      and form fewer, simpler neuromuscular junctions, which is the in vitro
      correlate of the peripheral arm seen in the complicated form.
    evidence:
    - reference: PMID:36359747
      reference_title: Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, NMJs from HSP-derived lines were lower in number and in
        contact point complexity, denoting an impaired NMJ profile
      explanation: >-
        Lower motor neurons from SPG3A (and SPG4) patients form impaired NMJs;
        the SPG3A and SPG4 lines were pooled in this readout.
- name: Presynaptic Dysfunction of Corticospinal Neurons
  biological_scale: CELLULAR
  description: >-
    Transcriptomic comparison of SPG3A patient iPSC-derived cortical projection
    neurons with controls identifies synaptic dysfunction as a top altered
    pathway beside lipid pathways: synaptic genes and proteins are reduced and
    calcium activity is diminished in neurons from two patients with different
    missense variants, and both are restored by the LXR agonist LXR623. In fly
    motor neurons, atlastin loss depletes presynaptic proteins at terminals and
    disturbs synaptic vesicle pools, with progressive decline in locomotion.
  cell_types:
  - preferred_term: corticospinal upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  biological_processes:
  - preferred_term: synapse organization
    term:
      id: GO:0050808
      label: synapse organization
    modifier: DECREASED
  evidence:
  - reference: PMID:41250225
    reference_title: LXR agonist rescues synaptic dysfunction and degeneration in SPG3A patient-specific iPSC-derived neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We observed significant reductions of synaptic genes and proteins in
      cortical PNs from both SPG3A-P342S and SPG3A-M408T patient iPSCs,
      emphasizing synaptic dysfunction in SPG3A neurons.
    explanation: Synaptic gene and protein loss in patient cortical projection neurons carrying two different variants.
  - reference: PMID:41250225
    reference_title: LXR agonist rescues synaptic dysfunction and degeneration in SPG3A patient-specific iPSC-derived neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Calcium imaging revealed a significant reduction of activity in SPG3A
      cortical neurons compared to control neurons, further supporting
      functional deficits in SPG3A neurons.
    explanation: The functional correlate of the synaptic protein loss.
  - reference: PMID:28860117
    reference_title: Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using Drosophila, we demonstrate that downregulation or overexpression of
      Atlastin in motor neurons results in decreased crawling speed and
      contraction frequency in larvae, while adult flies show progressive
      decline in climbing ability.
    explanation: Motor-neuron atlastin loss produces a progressive locomotor decline with presynaptic dysfunction in the fly.
  downstream:
  - target: Distal Length-Dependent Corticospinal Axon Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Synaptic failure and degeneration co-occur in the patient neuron model
      and are rescued together, but whether synaptic dysfunction precedes or
      follows axonal degeneration has not been resolved.
- name: Distal Length-Dependent Corticospinal Axon Degeneration
  conforms_to: "corticospinal_tract_axonopathy#Distal Length-Dependent Degeneration of Long CNS Axons"
  biological_scale: TISSUE
  description: >-
    The corticospinal axons reaching the lumbosacral cord, the longest in the
    central nervous system, degenerate from their distal ends in a retrograde,
    length-dependent pattern, so the deficit is maximal in the legs and the arms
    are largely spared. In SPG3A the corticospinal lesion is clinically
    evident from early childhood and is reflected in frequently abnormal motor
    evoked potentials, while the dorsal columns are involved in only a
    minority. Quantitative post-mortem study of HSP shows reduced corticospinal
    axon number at every level with the loss most pronounced distally, the
    signature of a dying-back axonopathy.
  cell_types:
  - preferred_term: corticospinal upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  biological_processes:
  - preferred_term: neuron projection maintenance
    term:
      id: GO:1990535
      label: neuron projection maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:15540998
    reference_title: The extent of axonal loss in the long tracts in hereditary spastic paraplegia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the corticospinal tracts, the ratio of medulla and lumbar total axonal
      number was significantly greater in HSP cases compared to controls
      suggesting more pronounced axonal loss in the distal neuraxis in HSP than
      in controls.
    explanation: >-
      The quantitative human neuropathology of the length-dependent
      corticospinal lesion; from six HSP post-mortems of unspecified genotype,
      so indirect for SPG3A.
  - reference: PMID:15540998
    reference_title: The extent of axonal loss in the long tracts in hereditary spastic paraplegia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings are consistent with a length-dependent 'dying back'
      axonopathy.
    explanation: The pathologists' own reading of the pattern as a dying-back axonopathy.
  - reference: PMID:18270207
    reference_title: Atlastin GTPases are required for Golgi apparatus and ER morphogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The hereditary spastic paraplegias (SPG1-33) comprise a cluster of
      inherited neurological disorders characterized principally by lower
      extremity spasticity and weakness due to a length-dependent, retrograde
      axonopathy of corticospinal motor neurons.
    explanation: >-
      States the length-dependent retrograde corticospinal axonopathy shared by
      the HSPs; cited as the framing of the SPG3A study rather than as a
      primary pathological observation.
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These particularities, as well as frequent abnormal motor evoked
      potentials, could help identify patients to be screened for atlastin1
      gene mutations.
    explanation: Abnormal motor evoked potentials are the clinical neurophysiological correlate of corticospinal tract dysfunction in SPG3A patients.
  - reference: PMID:35348668
    reference_title: Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Atl1KI/KI/Reep1-/- mice exhibit early onset and rapidly progressive
      declines in several motor function tests.
    explanation: The double-mutant mouse reproduces a progressive motor phenotype from a corticospinal ER lesion.
  downstream:
  - target: Loss of Supraspinal Inhibition of the Spinal Stretch Reflex
    causal_link_type: DIRECT
- name: Loss of Supraspinal Inhibition of the Spinal Stretch Reflex
  conforms_to: "corticospinal_tract_axonopathy#Loss of Supraspinal Inhibitory Control of the Stretch Reflex"
  biological_scale: TISSUE
  description: >-
    Loss of descending corticospinal input releases the lumbar stretch reflex
    from supraspinal inhibitory control, producing velocity-dependent
    hypertonia, hyperreflexia, clonus and extensor plantar responses. The step
    is the shared HSP mechanism carried by the module and is not separately
    evidenced for SPG3A.
  cell_types:
  - preferred_term: spinal motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  downstream:
  - target: Progressive Lower-Limb Spasticity and Weakness
    causal_link_type: DIRECT
- name: Progressive Lower-Limb Spasticity and Weakness
  conforms_to: "corticospinal_tract_axonopathy#Progressive Lower-Limb Spasticity and Weakness"
  biological_scale: ORGANISM
  description: >-
    Bilateral, largely symmetric spasticity and weakness of the legs presenting
    as a spastic gait, usually in the first decade, with slow and often
    near-static progression in SPG3A and preserved ambulation in most.
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by
      progressive bilateral and mostly symmetric spasticity and weakness of the
      legs.
    explanation: GeneReviews clinical characterization of the core syndrome.
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with SPG3A typically present a slow progression and remain
      ambulatory throughout their life.
    explanation: The typical slow course with preserved ambulation.
  downstream:
  - target: Spastic gait
    causal_link_type: DIRECT
  - target: Lower limb spasticity
    causal_link_type: DIRECT
  - target: Lower limb muscle weakness
    causal_link_type: DIRECT
- name: Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  biological_scale: TISSUE
  description: >-
    In the complicated form, and subclinically in further patients, the long
    peripheral motor and sensory axons also degenerate, producing an axonal
    sensorimotor neuropathy with lower motor neuron involvement and distal
    amyotrophy. This is the peripheral counterpart of the corticospinal lesion,
    conforming to the peripheral module at its axonal-degeneration node; there
    is no demyelinating component. The allelic disorder HSN1D shows that ATL1
    variants can injure long peripheral axons on their own.
  cell_types:
  - preferred_term: lower motor neuron
    term:
      id: CL:0008039
      label: lower motor neuron
  evidence:
  - reference: PMID:17502470
    reference_title: Hereditary spastic paraplegia 3A associated with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our electrophysiological and pathological findings confirmed an axonal
      sensory-motor neuropathy.
    explanation: Electrophysiology and nerve pathology establish the peripheral lesion as axonal and sensorimotor.
  - reference: PMID:25193411
    reference_title: Extremely severe complicated spastic paraplegia 3A with neonatal onset.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrophysiological studies revealed severe diffuse axonal neuropathy.
    explanation: A severe complicated case with diffuse axonal neuropathy.
  downstream:
  - target: Distal amyotrophy
    causal_link_type: DIRECT
  - target: Peripheral axonal neuropathy
    causal_link_type: DIRECT
phenotypes:
- name: Lower limb spasticity
  category: Neurological
  description: >-
    Progressive bilateral, mostly symmetric spasticity of the legs, the defining
    feature of the disorder.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by
      progressive bilateral and mostly symmetric spasticity and weakness of the
      legs.
    explanation: GeneReviews names lower-limb spasticity as the defining feature.
- name: Lower limb muscle weakness
  category: Neurological
  description: >-
    Weakness accompanies the spasticity in the legs; distally it typically
    affects foot dorsiflexion.
  phenotype_term:
    preferred_term: Lower limb muscle weakness
    term:
      id: HP:0007340
      label: Lower limb muscle weakness
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by
      progressive bilateral and mostly symmetric spasticity and weakness of the
      legs.
    explanation: GeneReviews pairs weakness with spasticity in the core description.
- name: Foot dorsiflexor weakness
  category: Neurological
  description: >-
    The distal weakness typically affects foot dorsiflexion and is the
    indication for ankle-foot orthoses.
  phenotype_term:
    preferred_term: Foot dorsiflexor weakness
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  frequency: FREQUENT
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distal weakness (typically affecting foot dorsiflexion) can be ameliorated
      by ankle-foot orthoses.
    explanation: GeneReviews identifies foot dorsiflexion as the typical site of distal weakness.
- name: Spastic gait
  category: Neurological
  description: >-
    Spastic gait is the usual presenting sign; the average age of onset is four
    years, more than 80% of reported individuals are symptomatic before the end
    of the first decade, and later onset is uncommon.
  phenotype_term:
    preferred_term: Spastic gait
    term:
      id: HP:0002064
      label: Spastic gait
    onset:
      onset_category: CHILDHOOD
      mean_age_years: 4
      notes: >-
        Average onset four years (GeneReviews); mean 4.6 +/- 3.9 years in the
        French series and 3 years in the Dutch-German series; onset ranged from
        1 to 68 years in Taiwan.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The average age of onset is four years. More than 80% of reported
      individuals manifest spastic gait before the end of the first decade of
      life.
    explanation: GeneReviews onset figures for the presenting spastic gait.
  - reference: PMID:16401858
    reference_title: SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPG3A was twice as frequent as SPG4 in patients with onset before age 10
      years (31.8%). Later onset was not observed.
    explanation: In the German cohort every SPG3A case began before age ten.
  - reference: PMID:17502470
    reference_title: Hereditary spastic paraplegia 3A associated with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In most cases, SPG3A mutations were associated with an early age at onset
      (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later
      (mean, 14 y) with clear intrafamilial variability (8-28 y).
    explanation: Records both the typical early onset and a later-onset family with intrafamilial variability.
  - reference: PMID:34015694
    reference_title: Clinical and genetic characterization of hereditary spastic paraplegia type 3A in Taiwan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They typically presented a pure form HSP phenotype with disease onset
      ranging from age 1-68 years.
    explanation: Adult onset occurs but is uncommon; the Taiwanese range spans 1 to 68 years.
- name: Hyperreflexia
  category: Neurological
  description: >-
    Lower-limb hyperreflexia with extensor plantar responses is part of the
    upper motor neuron syndrome common to the HSPs. Compared with SPG4,
    increased reflexes in the upper limbs are less frequent in SPG3A.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:34831093
    reference_title: ER Morphology in the Pathogenesis of Hereditary Spastic Paraplegia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      The severity of these symptoms varies among patients, and they are often
      accompanied by lower-extremity hyperreflexia and extensor plantar
      responses.
    explanation: >-
      A statement about HSP in general, applied to SPG3A as a pure HSP; the
      quote is from the full text of a review rather than an SPG3A cohort.
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPG3A patients had earlier symptom onset, less frequently increased
      reflexes in the upper limbs, decreased vibration sense in the lower limbs,
      and fewer sphincter disturbances, but more frequently observed wasting in
      the lower limbs and scoliosis.
    explanation: The comparison with SPG4 that distinguishes the SPG3A reflex pattern.
- name: Babinski sign
  category: Neurological
  description: >-
    Extensor plantar responses accompany the lower-limb hyperreflexia of the
    corticospinal syndrome.
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  evidence:
  - reference: PMID:34831093
    reference_title: ER Morphology in the Pathogenesis of Hereditary Spastic Paraplegia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      The severity of these symptoms varies among patients, and they are often
      accompanied by lower-extremity hyperreflexia and extensor plantar
      responses.
    explanation: A general HSP statement applied to SPG3A as a pure HSP; quoted from the review's full text.
- name: Abnormal motor evoked potentials
  category: Neurological
  description: >-
    Motor evoked potentials are frequently abnormal, reflecting corticospinal
    tract dysfunction, and were proposed as a marker for selecting patients for
    ATL1 testing.
  phenotype_term:
    preferred_term: Abnormal motor evoked potentials
    term:
      id: HP:0012896
      label: Abnormal motor evoked potentials
  frequency: FREQUENT
  evidence:
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These particularities, as well as frequent abnormal motor evoked
      potentials, could help identify patients to be screened for atlastin1
      gene mutations.
    explanation: The French series reports frequent abnormal motor evoked potentials in SPG3A.
- name: Impaired vibratory sensation
  category: Neurological
  description: >-
    Diminished vibration sense from dorsal-column involvement is present in a
    minority of individuals with SPG3A, in contrast to its near-universal
    presence in other dominant HSPs such as SPG4.
  phenotype_term:
    preferred_term: Impaired vibratory sensation
    term:
      id: HP:0002495
      label: Impaired vibratory sensation
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to other forms of autosomal dominant hereditary spastic
      paraplegia (HSP), in which diminished vibration sense (caused by
      degeneration of the corticospinal tracts and dorsal columns) and urinary
      bladder hyperactivity are present in all affected individuals, these
      findings occur in a minority of individuals with SPG3A.
    explanation: GeneReviews places dorsal-column sensory loss in a minority of SPG3A cases.
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, additional signs such as decreased vibration sense and wasting in
      lower limbs, sphincter disturbances, and scoliosis were found in a
      minority of patients.
    explanation: The French series confirms decreased vibration sense in a minority.
- name: Urinary urgency
  category: Genitourinary
  description: >-
    Bladder hyperactivity with urgency occurs in a minority of individuals,
    unlike in other dominant HSPs where it is nearly universal; it responds to
    anticholinergic antispasmodics.
  phenotype_term:
    preferred_term: Urinary urgency
    term:
      id: HP:0000012
      label: Urinary urgency
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to other forms of autosomal dominant hereditary spastic
      paraplegia (HSP), in which diminished vibration sense (caused by
      degeneration of the corticospinal tracts and dorsal columns) and urinary
      bladder hyperactivity are present in all affected individuals, these
      findings occur in a minority of individuals with SPG3A.
    explanation: GeneReviews places bladder hyperactivity in a minority of SPG3A cases.
- name: Scoliosis
  category: Skeletal
  description: >-
    Scoliosis, a secondary consequence of the chronic spastic paraparesis, is
    found in a minority of patients and is more frequent than in SPG4.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, additional signs such as decreased vibration sense and wasting in
      lower limbs, sphincter disturbances, and scoliosis were found in a
      minority of patients.
    explanation: Scoliosis in a minority of the French SPG3A patients.
- name: Distal amyotrophy
  category: Neurological
  description: >-
    Lower motor neuron involvement in the complicated (Silver syndrome)
    phenotype produces distal muscle wasting, most often in the lower limbs;
    wasting in the lower limbs is more frequent in SPG3A than in SPG4.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  frequency: OCCASIONAL
  subtype: Complicated SPG3A
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      complicated HSP with axonal motor neuropathy and/or distal amyotrophy with
      lower motor neuron involvement (Silver syndrome phenotype) has been
      observed.
    explanation: GeneReviews documents distal amyotrophy in the complicated phenotype.
  - reference: PMID:22378671
    reference_title: Very early onset and severe complicated phenotype caused by a new spastic paraplegia 3A gene mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the last neurologic examination performed at 17 years of life, the
      patient disclosed spastic tetraparesis, sensorimotor axonal neuropathy,
      cognitive and cranial nerve impairment, mild pes cavus, and distal
      amyotrophy.
    explanation: Distal amyotrophy in a severe complicated case.
- name: Peripheral axonal neuropathy
  category: Neurological
  description: >-
    An axonal sensorimotor neuropathy, confirmed electrophysiologically and
    pathologically, accompanied the spastic paraplegia in about 17% of
    mutation carriers in one 182-family screen, with no genotype predicting
    it; a motor axonal neuropathy in a
    young child can mimic diplegic cerebral palsy.
  phenotype_term:
    preferred_term: axonal sensorimotor neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  frequency: OCCASIONAL
  subtype: Complicated SPG3A
  evidence:
  - reference: PMID:17502470
    reference_title: Hereditary spastic paraplegia 3A associated with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W)
      originating from 5 unrelated families presented with a complex form of
      hereditary spastic paraplegia associated with a neuropathy (17%). Our
      electrophysiological and pathological findings confirmed an axonal
      sensory-motor neuropathy.
    explanation: Frequency and axonal sensorimotor character of the neuropathy.
  - reference: PMID:19735987
    reference_title: Hereditary spastic paraplegia and axonal motor neuropathy caused by a novel SPG3A de novo mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a new heterozygous S398F mutation in exon 12 of the SPG3A gene
      causing a very early-onset spastic paraplegia in association with motor
      axonal neuropathy in a 4-year-old girl resembling diplegic cerebral palsy.
    explanation: A de novo case with motor axonal neuropathy that mimicked cerebral palsy.
- name: Dystonia
  category: Neurological
  description: >-
    Dystonia is one of the genotype-specific movement disorders of early-onset
    HSP and is associated with SPG3A, alongside SPG4 and the AP-4 HSPs; it is
    also part of the severe complex presentation.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:41328529
    reference_title: "Spectrum of Movement Disorders in Early-Onset Hereditary Spastic Paraplegia: A Study of 428 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distinct genotype-specific patterns were observed: dystonia in SPG4,
      SPG3A, and AP-4-HSP; parkinsonism in SPG11; and ataxia in SPG15, SPG76,
      SPG7, SPG5a, and SPG46.
    explanation: A 428-case natural-history study associates dystonia with the SPG3A genotype; frequency within SPG3A is not given, so none is recorded.
- name: Axial hypotonia
  category: Neurological
  description: >-
    In the severe very-early-onset complex form, axial hypotonia in the first
    months of life precedes the emergence of limb spasticity.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
    onset:
      onset_category: INFANTILE
  frequency: VERY_RARE
  subtype: Severe early-onset complex SPG3A
  evidence:
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report three unrelated individuals presenting with very-early-onset
      (before 7 months) complex, and severe HSP phenotypes (axial hypotonia,
      spastic quadriplegia, dystonia, seizures and intellectual disability).
    explanation: Axial hypotonia in the three very-early-onset cases.
- name: Spastic tetraplegia
  category: Neurological
  description: >-
    Four-limb spasticity, rather than the paraplegia of typical SPG3A, marks
    the severe very-early-onset complex form.
  phenotype_term:
    preferred_term: Spastic quadriplegia
    term:
      id: HP:0002510
      label: Spastic tetraplegia
  frequency: VERY_RARE
  subtype: Severe early-onset complex SPG3A
  evidence:
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report three unrelated individuals presenting with very-early-onset
      (before 7 months) complex, and severe HSP phenotypes (axial hypotonia,
      spastic quadriplegia, dystonia, seizures and intellectual disability).
    explanation: Spastic quadriplegia in the very-early-onset cases.
  - reference: PMID:22378671
    reference_title: Very early onset and severe complicated phenotype caused by a new spastic paraplegia 3A gene mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the last neurologic examination performed at 17 years of life, the
      patient disclosed spastic tetraparesis, sensorimotor axonal neuropathy,
      cognitive and cranial nerve impairment, mild pes cavus, and distal
      amyotrophy.
    explanation: Spastic tetraparesis in a P344S very-early-onset case.
- name: Intellectual disability
  category: Neurodevelopmental
  description: >-
    Neurodevelopmental abnormalities including intellectual disability are
    prevalent among patients with variants in the three-dimensional mutational
    cluster and in the biallelic cases; they are absent from typical SPG3A.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_RARE
  subtype: Severe early-onset complex SPG3A
  evidence:
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report three unrelated individuals presenting with very-early-onset
      (before 7 months) complex, and severe HSP phenotypes (axial hypotonia,
      spastic quadriplegia, dystonia, seizures and intellectual disability).
    explanation: Intellectual disability in the very-early-onset cases.
  - reference: PMID:37927245
    reference_title: "A novel homozygous variant in ATL1 associated with early onset spastic paraplegia 3A: Further evidence for autosomal recessive inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The infant's phenotype is consistent with an early onset complicated
      SPG3A with severe progressive spasticity of the lower limbs and
      intellectual disability.
    explanation: Intellectual disability in a homozygous splice-variant case.
- name: Seizure
  category: Neurological
  description: >-
    Seizures occur in the severe very-early-onset complex form and are not a
    feature of typical SPG3A.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  frequency: VERY_RARE
  subtype: Severe early-onset complex SPG3A
  evidence:
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report three unrelated individuals presenting with very-early-onset
      (before 7 months) complex, and severe HSP phenotypes (axial hypotonia,
      spastic quadriplegia, dystonia, seizures and intellectual disability).
    explanation: Seizures in the very-early-onset cases.
- name: Pseudobulbar paralysis
  category: Neurological
  description: >-
    Bulbar symptoms belong to the mutational-cluster phenotype; in the most
    severe neonatal-onset case pseudobulbar palsy severely impaired speech,
    chewing and swallowing.
  phenotype_term:
    preferred_term: Pseudobulbar palsy
    term:
      id: HP:0007024
      label: Pseudobulbar paralysis
  frequency: VERY_RARE
  subtype: Severe early-onset complex SPG3A
  evidence:
  - reference: PMID:25193411
    reference_title: Extremely severe complicated spastic paraplegia 3A with neonatal onset.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also developed with pseudobulbar palsy; his speech, chewing, and
      swallowing were severely impaired.
    explanation: Pseudobulbar palsy in the neonatal-onset G409D case.
- name: Dysphagia
  category: Neurological
  description: >-
    Swallowing problems are part of the bulbar involvement of the severe
    very-early-onset complex form; all three very-early-onset cases had them.
  phenotype_term:
    preferred_term: Swallowing problems
    term:
      id: HP:0002015
      label: Dysphagia
  frequency: VERY_RARE
  subtype: Severe early-onset complex SPG3A
  evidence:
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, we report here the cases of 3 patients with severe forms
      of early-onset SPG3A, offering detailed descriptions of this poorly known
      phenotype made of neonatal hypotonia, secondary limbs spasticity (spastic
      para or tetraplegia), developmental delay, speech and swallowing problems.
    explanation: Swallowing problems in the authors' summary of the severe phenotype; quoted from the full text.
- name: Dysarthria
  category: Neurological
  description: >-
    Speech impairment, in one case attributed to facial hypotonia, accompanies
    the swallowing difficulty of the severe very-early-onset complex form.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  frequency: VERY_RARE
  subtype: Severe early-onset complex SPG3A
  evidence:
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarly to previous patients, he also presented with swallowing
      problems and dysarthria.
    explanation: Dysarthria in the third very-early-onset case; quoted from the full text.
- name: Abnormal cerebral white matter morphology
  category: Neurological
  description: >-
    Brain imaging abnormalities belong to the mutational-cluster phenotype. In
    the very-early-onset cases MRI showed white matter T2 hyperintensities
    read as delayed myelination in two children and was normal in the third;
    the umbrella HSP entry also records a thin corpus callosum in SPG3A. MRI
    is normal in typical pure SPG3A.
  phenotype_term:
    preferred_term: white matter T2 hyperintensities with delayed myelination
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  frequency: VERY_RARE
  subtype: Severe early-onset complex SPG3A
  evidence:
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Indeed, brain MRI at 5 years revealed white matter T2 hyperintensities
      evocative of myelination delay
    explanation: The imaging finding in the second very-early-onset case; quoted from the full text.
  - reference: PMID:35925862
    reference_title: De novo variants cause complex symptoms in HSP-ATL1 (SPG3A) and uncover genotype-phenotype correlations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Establishing genotype-phenotype correlations, we find that symptoms that
      extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental
      abnormalities, upper limb spasticity, bulbar symptoms, peripheral
      neuropathy and brain imaging abnormalities) are prevalent in patients with
      variants located within this mutational cluster.
    explanation: Brain imaging abnormalities are part of the cluster phenotype across 537 cases.
genetic:
- name: ATL1
  gene_term:
    preferred_term: ATL1
    term:
      id: hgnc:11231
      label: ATL1
  relationship_type: CAUSATIVE
  notes: >-
    Heterozygous ATL1 variants, almost all missense, are found in essentially
    every SPG3A proband; most lie in the exons encoding the GTPase domain and
    three-helix bundle (exons 4, 7, 8, 12 and 13 in the two largest series),
    and most are private, although R239C recurs across populations and R416C is
    a founder allele in Taiwan. Copy-number and truncating variants are rare.
    Two families with biallelic variants were the recorded exception when
    GeneReviews was last updated; several more homozygous families have since
    been described.
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of ATL1-HSP is established in a proband with suggestive
      findings and almost exclusively a heterozygous pathogenic variant in ATL1
      identified by molecular genetic testing.
    explanation: GeneReviews establishes heterozygous ATL1 variants as the molecular basis.
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far, most mutations have been private, although they were all found in
      exons 7, 8, 12, and 13.
    explanation: Private missense variants clustered in four exons in the French series.
  - reference: PMID:31594988
    reference_title: Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 10 detected ATL1 mutations were missense substitutions, most of which
      were in the mutational hot spots of 4, 7, 8, 12 exons, with 2 novel
      mutations.
    explanation: The Russian cohort confirms an all-missense spectrum in the same hotspot exons.
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study enables us to estimate the frequency of the SPG3A mutations in
      France at 39% in families with young-onset autosomal dominant spastic
      paraplegia after exclusion of SPG4 cases.
    explanation: ATL1 accounts for 39% of young-onset dominant HSP families once SPG4 is excluded.
  - reference: PMID:34782662
    reference_title: Clinical and molecular characterization of a large cohort of childhood onset hereditary spastic paraplegias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common childhood-onset subtype was SPG4, 11/50 (22%) families
      with solved genetic diagnosis; followed by SPG3A, 8/50 (16%).
    explanation: SPG3A is the second most common solved cause of childhood-onset HSP in Brazil.
  - reference: PMID:34015694
    reference_title: Clinical and genetic characterization of hereditary spastic paraplegia type 3A in Taiwan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPG3A accounts for 4% (11 out of 274) of HSP in the Taiwanese cohort.
    explanation: The ATL1 share of an unselected East Asian HSP cohort.
  variants:
  - name: p.Arg239Cys (R239C)
    description: >-
      The most frequently identified SPG3A variant, recurring across European
      and East Asian cohorts. It disrupts BMPRII trafficking in a
      dominant-negative manner, yet shows wild-type ER network formation,
      GTPase activity, dimerisation and membrane fusion in every assay, which
      is the principal evidence that a fusion deficit is not required for
      disease.
    evidence:
    - reference: PMID:25761634
      reference_title: ER network formation and membrane fusion by atlastin1/SPG3A disease variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Surprisingly however, at least two disease variants, one of which
        represents that most frequently identified in SPG3A HSP patients,
        displayed wild-type levels of activity in all assays.
      explanation: The most frequent variant retains full activity in cell-based and biochemical assays.
    - reference: PMID:23079343
      reference_title: Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Endogenous and expressed atlastin-1 showed a strong interaction with BMP
        receptors II (BMPRII) and analyzed missense, HSP-causing mutations R239C
        and R495W disrupted BMPRII trafficking to the cell surface.
      explanation: The same variant has a measurable fusion-independent effect on BMPRII trafficking.
    - reference: PMID:34015694
      reference_title: Clinical and genetic characterization of hereditary spastic paraplegia type 3A in Taiwan.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Five heterozygous ATL1 mutations were identified, including p.R239C,
        p.V253I, p.Y336H, p.P342R and p.R416C.
      explanation: R239C recurs in the Taiwanese cohort.
  - name: p.Arg416Cys (R416C), Taiwanese founder allele
    description: >-
      The most common ATL1 variant in Taiwan, found in five pedigrees sharing
      a haplotype consistent with a common ancestor.
    evidence:
    - reference: PMID:34015694
      reference_title: Clinical and genetic characterization of hereditary spastic paraplegia type 3A in Taiwan.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ATL1 p.R416C was the most common mutation and presented in five SPG3A
        pedigrees. Haplotype analyses demonstrated a shared haplotype in the 12
        individuals carrying a p.R416C allele.
      explanation: Founder evidence from shared haplotype analysis.
  - name: p.Arg118Gln (R118Q), homozygous
    description: >-
      A homozygous GTPase-domain missense variant segregating with early-onset
      HSP in six members of a consanguineous family; seven heterozygous
      carriers were clinically unaffected.
    evidence:
    - reference: PMID:24473461
      reference_title: Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole-exome sequencing and segregation analysis revealed a homozygous
        novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six
        affected family members.
      explanation: The first recessive SPG3A allele.
  - name: p.Pro342Ser (P342S)
    description: >-
      A variant in the hinge between the GTPase and assembly domains, found in
      a girl with pure SPG3A and used to derive the first SPG3A patient iPSC
      neuronal model; the same patient line underlies the later lipid and
      synaptic studies.
    evidence:
    - reference: PMID:24908668
      reference_title: Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We have identified a p.Pro342Ser mutation in a young girl with pure
        SPG3A. This residue is in a critical hinge region of atlastin-1 between
        its GTPase and assembly domains, and it is conserved in all known
        eukaryotic atlastin orthologs.
      explanation: Identifies the variant, its location and its conservation.
  - name: p.Lys406Glu (K406E), de novo
    description: >-
      A de novo three-helix-bundle variant in one of the three very-early-onset
      severe complex cases.
    evidence:
    - reference: PMID:39003427
      reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These individuals carried novel ATL1 pathogenic variants (a de novo ATL1
        missense p.(Lys406Glu), a homozygous frameshift p.(Arg403Glufs*3) and a
        homozygous missense variant (p.Tyr367His)).
      explanation: The de novo variant among the severe cases.
diagnosis:
- name: Molecular genetic testing for ATL1
  description: >-
    The diagnosis is established in a proband with suggestive findings by
    identifying a heterozygous pathogenic ATL1 variant, almost exclusively;
    biallelic variants are the rare exception. In practice testing is by a
    multigene HSP panel or exome, since the pure early-onset phenotype overlaps
    with SPG4 and the severe complex phenotype with cerebral palsy. Directed
    single-gene screening should be used with caution because recessive
    families exist.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of ATL1-HSP is established in a proband with suggestive
      findings and almost exclusively a heterozygous pathogenic variant in ATL1
      identified by molecular genetic testing.
    explanation: The GeneReviews confirmatory-testing criterion.
  - reference: PMID:24473461
    reference_title: Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This apparent autosomal recessive inheritance adds to the clinical
      complexity of spastic paraplegia 3A and calls for caution using directed
      genetic screening in HSP.
    explanation: The recessive family's authors warn against pedigree-directed screening.
- name: Electromyography and nerve conduction studies
  description: >-
    Electrophysiology detects the axonal sensorimotor neuropathy of the
    complicated form, including subclinical involvement, and grades its
    severity in the complex cases.
  diagnosis_term:
    preferred_term: electromyography and nerve conduction studies
    term:
      id: NCIT:C38056
      label: Electromyography
  evidence:
  - reference: PMID:17502470
    reference_title: Hereditary spastic paraplegia 3A associated with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our electrophysiological and pathological findings confirmed an axonal
      sensory-motor neuropathy.
    explanation: Electrophysiology is how the neuropathy was characterised.
  - reference: PMID:25193411
    reference_title: Extremely severe complicated spastic paraplegia 3A with neonatal onset.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrophysiological studies revealed severe diffuse axonal neuropathy.
    explanation: Electrophysiology grading the neuropathy in a severe case.
- name: Brain MRI
  description: >-
    Brain MRI is normal in typical pure SPG3A and serves to exclude structural,
    inflammatory and demyelinating mimics; in a young child labelled cerebral
    palsy, the absence of MRI changes congruent with that diagnosis is what
    should prompt genetic testing. In the severe complex form MRI may show
    white matter T2 hyperintensities with delayed myelination.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarly to patient 1, this individual was first diagnosed with CP until
      follow-up in an expert center and the lack of congruent brain MRI
      abnormalities motivated further tests.
    explanation: MRI incongruent with cerebral palsy as the trigger for genetic testing; quoted from the full text.
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI performed at the age of 2 years was normal.
    explanation: A normal MRI in one severe case, so a normal scan does not exclude SPG3A; quoted from the full text.
- name: Motor evoked potentials
  description: >-
    Transcranial magnetic stimulation motor evoked potentials are frequently
    abnormal and were proposed, together with the clinical particularities, as
    a way to select young-onset dominant HSP patients for ATL1 testing.
  diagnosis_term:
    preferred_term: motor evoked potentials
  evidence:
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These particularities, as well as frequent abnormal motor evoked
      potentials, could help identify patients to be screened for atlastin1
      gene mutations.
    explanation: Motor evoked potentials as a screening aid for SPG3A.
differential_diagnoses:
- name: Cerebral palsy
  description: >-
    Spastic diplegic cerebral palsy is the recurrent initial misdiagnosis of
    early-onset SPG3A, and the severe very-early-onset complex form with
    quadriplegia, dystonia and seizures mimics it closely. A family history,
    progression, or the absence of a perinatal insult should prompt genetic
    testing.
  disease_term:
    preferred_term: cerebral palsy
    term:
      id: MONDO:0006497
      label: cerebral palsy
  evidence:
  - reference: PMID:39003427
    reference_title: "Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their ability to mimic CP also implies that genetic testing should be
      considered for patients with atypical forms of CP, given the implications
      for genetic counseling.
    explanation: The authors' explicit recommendation that atypical cerebral palsy be genetically tested.
  - reference: PMID:25193411
    reference_title: Extremely severe complicated spastic paraplegia 3A with neonatal onset.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He manifested general hypertonia and hypokinesia since the neonatal period
      and was initially diagnosed with cerebral palsy.
    explanation: A neonatal-onset case first labelled cerebral palsy.
- name: Hereditary spastic paraplegia 4 (SPG4)
  description: >-
    The most common dominant HSP and the main alternative in a dominant family
    with pure spastic paraplegia. SPG3A has earlier onset, less frequent
    upper-limb hyperreflexia, less dorsal-column and sphincter involvement, and
    more lower-limb wasting and scoliosis; below age ten SPG3A is twice as
    frequent as SPG4.
  evidence:
  - reference: PMID:15596607
    reference_title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPG3A patients had earlier symptom onset, less frequently increased
      reflexes in the upper limbs, decreased vibration sense in the lower limbs,
      and fewer sphincter disturbances, but more frequently observed wasting in
      the lower limbs and scoliosis.
    explanation: The head-to-head clinical comparison with 126 SPG4 patients.
  - reference: PMID:16401858
    reference_title: SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPG3A was twice as frequent as SPG4 in patients with onset before age 10
      years (31.8%).
    explanation: Onset before ten favours SPG3A over SPG4.
- name: Hereditary sensory neuropathy type 1D (HSN1D)
  description: >-
    The allelic disorder: dominant ATL1 variants that present as a
    predominantly sensory axonal neuropathy with painless injuries rather than
    as spastic paraplegia. Reduced GTPase activity and a disrupted ER network
    are documented for the HSN1D allele and for many, though not all, SPG3A
    alleles; what determines whether sensory or motor long axons degenerate is
    unresolved. Curated in the separate Hereditary_Sensory_Neuropathy_Type_1D
    entry.
  disease_term:
    preferred_term: hereditary sensory neuropathy type 1D
    term:
      id: MONDO:0013381
      label: "neuropathy, hereditary sensory, type 1D"
  evidence:
  - reference: PMID:21194679
    reference_title: "Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study highlights an unexpected major role for atlastin-1 in the
      function of sensory neurons and identifies HSN I and SPG3A as allelic
      disorders.
    explanation: Establishes HSN1D and SPG3A as allelic disorders.
- name: Silver syndrome (SPG17) and other complicated HSPs with distal amyotrophy
  description: >-
    Spastic paraplegia with distal wasting of the hand muscles defines Silver
    syndrome, classically linked to BSCL2 at the SPG17 locus and clinically and
    genetically heterogeneous; the same phenotype has been reported with ATL1
    and SPAST variants, so the complicated SPG3A subtype cannot be separated
    from SPG17 on clinical grounds.
  evidence:
  - reference: PMID:15372247
    reference_title: "A clinical, genetic and candidate gene study of Silver syndrome, a complicated form of hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Silver syndrome (SS) is a complicated form of hereditary spastic
      paraplegia associated with distal wasting of the small muscles of the
      hands.
    explanation: Defines the Silver syndrome phenotype that the complicated SPG3A subtype resembles.
  - reference: PMID:19730024
    reference_title: Novel SPG3A and SPG4 mutations in two patients with Silver syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases suggest that Silver syndrome may be associated with a wider
      variety of genotypes than previously described.
    explanation: A Silver phenotype with an ATL1 variant, showing the clinical overlap.
treatments:
- name: Oral antispasticity pharmacotherapy
  description: >-
    Treatment is symptomatic. Medical treatment of spasticity begins with oral
    baclofen or tizanidine. Dantrolene should be avoided because it can induce
    irreversible weakness that adversely affects mobility. Across HSP there is
    no specific therapy and the evidence base for symptomatic drugs is thin;
    the one well-designed antispastic trial, of gabapentin, was negative.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
    - preferred_term: tizanidine
      term:
        id: CHEBI:63629
        label: tizanidine
  target_phenotypes:
  - preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  target_mechanisms:
  - target: Loss of Supraspinal Inhibition of the Spinal Stretch Reflex
    description: >-
      Baclofen and tizanidine dampen the disinhibited spinal stretch reflex
      rather than acting on the axonopathy.
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment is symptomatic. Medical treatment of spasticity may begin with
      oral baclofen or tizanidine
    explanation: GeneReviews first-line antispasticity recommendation.
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Dantrolene, as it can induce irreversible
      weakness, adversely affecting mobility.
    explanation: GeneReviews drug-safety warning reflected in the treatment description.
  - reference: PMID:30723448
    reference_title: "Management of Hereditary Spastic Paraplegia: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There currently exist no specific therapies for HSP, and treatment is
      exclusively symptomatic, aimed at reducing muscle spasticity, and
      improving strength and gait.
    explanation: The systematic review's framing that all HSP treatment is symptomatic.
  - reference: PMID:30723448
    reference_title: "Management of Hereditary Spastic Paraplegia: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the study evaluating gabapentin efficacy was well-designed, but failed to
      demonstrate any significant improvement.
    explanation: The negative gabapentin trial, cited so the entry does not imply antispastic drugs are trial-proven.
- name: Botulinum toxin chemodenervation
  description: >-
    Chemodenervation with botulinum A or B toxin is the next step for focal
    spasticity when oral antispasticity medications are not tolerated.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: botulinum toxin type A (or type B)
      term:
        id: CHEBI:3160
        label: Botulinum toxin type A
  target_phenotypes:
  - preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      followed by chemodenervation with botulinum A or B toxins if oral
      antispasticity medications are not tolerated.
    explanation: GeneReviews second-line recommendation.
- name: Intrathecal baclofen pump
  description: >-
    An intrathecal baclofen pump may be considered for individuals who improve
    on oral baclofen but have significant systemic adverse effects.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: intrathecal baclofen pump therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
  target_phenotypes:
  - preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrathecal baclofen pump may be considered for those who improve on oral
      baclofen but have significant systemic adverse effects.
    explanation: GeneReviews indication for the intrathecal route.
- name: Physical therapy
  description: >-
    Medical therapy is combined with intensive physical therapy focused on
    stretching and strengthening exercises, which may help delay or minimise
    muscle-tendon contractures, scoliosis and foot deformities.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Medical therapy should be combined with intensive physical therapy focused
      on stretching and strengthening exercises that may help delay or minimize
      muscle tendon contractures, scoliosis, and foot deformities.
    explanation: GeneReviews physical-therapy recommendation and its intended targets.
- name: Ankle-foot orthoses
  description: >-
    Distal weakness, typically of foot dorsiflexion, is ameliorated by
    ankle-foot orthoses.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: ankle-foot orthosis fitting
    term:
      id: NCIT:C15315
      label: Rehabilitation
  target_phenotypes:
  - preferred_term: Foot dorsiflexor weakness
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distal weakness (typically affecting foot dorsiflexion) can be ameliorated
      by ankle-foot orthoses.
    explanation: GeneReviews orthotic recommendation.
  notes: >-
    NCIT has no clinical-action term for orthosis use; the device concept is
    carried in preferred_term and the binding is to the rehabilitation action.
- name: Anticholinergic antispasmodic pharmacotherapy for urinary urgency
  description: >-
    Urinary urgency, present in a minority, is treated with anticholinergic
    antispasmodic drugs.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticholinergic agent
      term:
        id: NCIT:C66880
        label: Anticholinergic Agent
  target_phenotypes:
  - preferred_term: Urinary urgency
    term:
      id: HP:0000012
      label: Urinary urgency
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urinary urgency can be treated with anticholinergic antispasmodic drugs.
    explanation: GeneReviews bladder recommendation.
- name: Genetic counselling and surveillance
  description: >-
    Once the familial ATL1 variant is known, prenatal and preimplantation
    genetic testing are possible; counselling must address incomplete
    penetrance, de novo variants and the rare recessive form. Reevaluation once
    or twice yearly to identify and treat new complications is recommended.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      prenatal testing for a pregnancy at increased risk and preimplantation
      genetic testing are possible.
    explanation: GeneReviews reproductive options once the familial variant is known.
  - reference: PMID:20862796
    reference_title: Spastic Paraplegia 3A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      reevaluation once or twice yearly to identify and treat new complications
      is recommended.
    explanation: GeneReviews surveillance recommendation.
animal_models:
- name: Atl1 K80A knock-in / Reep1 knockout double-mutant mouse
  species: Mus musculus
  genotype: Atl1 K80A/K80A knock-in (GTPase-dead) on a Reep1 -/- background
  genes:
  - preferred_term: ATL1
    term:
      id: hgnc:11231
      label: ATL1
  description: >-
    The first robust rodent HSP model. Atlastin-1 carries a K80A knock-in that
    abolishes GTPase activity and its binding partner Reep1 is knocked out;
    single mutants are mild, but the double mutant develops early-onset,
    rapidly progressive motor decline, and its corticospinal axons show a
    dosage-dependent transverse, periodic expansion of the ER into a
    ladder-like structure on FIB-SEM reconstruction, with fragmented axonal
    mitochondria and hypophosphorylated neurofilaments.
  publication: PMID:35348668
  modeled_mechanisms:
  - target: Disrupted Tubular ER Network in Neurons
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The only in vivo observation of the ER of corticospinal axons under
      atlastin-1 GTPase loss; the ER is disorganised but expands rather than
      fragments.
    limitations: >-
      The lesion is a homozygous GTPase-dead knock-in combined with loss of
      Reep1, not a heterozygous patient missense allele, and the axonal ER
      expands rather than fragments; it is not known which change patient axons
      show.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        Patients carry one heterozygous ATL1 missense allele; the mouse is
        homozygous for an engineered GTPase-dead allele and lacks Reep1, so the
        genotype models the pathway rather than the human dosage.
    readouts:
    - name: Transverse ER expansion in corticospinal axons (FIB-SEM)
      target: Disrupted Tubular ER Network in Neurons
      direction: INCREASED
      interpretation: >-
        Structural readout of the axonal ER lesion, dosage-dependent across the
        mutant genotypes.
      evidence:
      - reference: PMID:35348668
        reference_title: Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Also, ER in mutant corticospinal axons dramatically expands
          transversely and periodically in a mutation dosage-dependent manner to
          create a ladder-like appearance
        explanation: Reports the FIB-SEM measurement behind this readout.
    - name: Axonal mitochondrial fragmentation and neurofilament hypophosphorylation
      target: Disrupted Tubular ER Network in Neurons
      direction: INCREASED
      interpretation: >-
        Organelle and cytoskeletal changes that track the ER change, linking
        the ER lesion to the transport arm.
      evidence:
      - reference: PMID:35348668
        reference_title: Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In lockstep with changes in ER morphology, axonal mitochondria are
          fragmented and proportions of hypophosphorylated neurofilament H and M
          subunits are dramatically increased in Atl1KI/KI/Reep1-/- spinal cord.
        explanation: Reports the mitochondrial and neurofilament measurements.
    evidence:
    - reference: PMID:35348668
      reference_title: Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we have generated a robust, double mutant mouse model of HSP in
        which atlastin-1 is genetically modified with a K80A knock-in (KI)
        missense change that abolishes its GTPase activity, whereas its binding
        partner Reep1 is knocked out.
      explanation: Describes the model whose corticospinal ER is informative for this node.
  - target: Progressive Lower-Limb Spasticity and Weakness
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Early-onset, rapidly progressive motor decline on several tests, as a
      correlate of the human motor syndrome.
    limitations: >-
      Motor test decline in a mouse is not spasticity, and the course is rapid
      rather than the slow, near-static course of typical SPG3A.
    readouts:
    - name: Motor function test performance
      target: Progressive Lower-Limb Spasticity and Weakness
      direction: DECREASED
      interpretation: Behavioural correlate of the corticospinal lesion.
      evidence:
      - reference: PMID:35348668
        reference_title: Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Atl1KI/KI/Reep1-/- mice exhibit early onset and rapidly progressive
          declines in several motor function tests.
        explanation: Reports the motor measurements behind this readout.
- name: Drosophila atlastin loss-of-function models
  species: Drosophila melanogaster
  genotype: atl null (atl2), motor-neuron-specific atl RNAi, and CRISPR knock-in patient variants in endogenous atl
  description: >-
    The fly has a single atlastin orthologue, so loss of function is
    interpretable. Atlastin loss fragments the ER, and flies lacking atl or
    depleted of it in motor neurons show reduced larval crawling, progressive
    adult climbing decline, abnormally distributed axonal secretory organelles
    and depleted presynaptic terminals. Patient variants knocked into the
    endogenous gene reduce atlastin activity to different degrees and, when
    overexpressed over wild type, do not behave as dominant negatives. Flies
    carrying homologues of pure-HSP versus complex-HSP patient variants differ
    in severity and in cellular lesion: the pure-variant models accumulate lipid
    droplets in long motor nerves and respond partially to an LXR agonist,
    while the complex-variant models show neuronal ER disruption without a
    lipid phenotype and no LXR response. The null also shows age-dependent
    dopaminergic neuron death, which has no human counterpart.
  publication: PMID:19633650
  modeled_mechanisms:
  - target: Disrupted Tubular ER Network in Neurons
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Loss of the fly atlastin fragments the ER, the defining cellular lesion.
    limitations: >-
      A null in an invertebrate with one atlastin; the human neuron expresses
      three paralogues, and the patient lesion is a heterozygous missense allele.
    evidence:
    - reference: PMID:19633650
      reference_title: Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here we demonstrate that Drosophila Atlastin--the fly homologue of the
        mammalian GTPase atlastin 1 involved in hereditary spastic
        paraplegia--localizes on ER membranes and that its loss causes ER
        fragmentation.
      explanation: The in vivo ER fragmentation on atlastin loss.
  - target: ATL1 Variant Impairing the Atlastin-1 GTPase Cycle
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Patient missense variants introduced into the endogenous fly gene test
      the functional consequence of each allele in vivo.
    limitations: >-
      Residues were transferred by alignment to the fly protein; the
      loss-of-function conclusion may not hold for human atlastin-1 in a
      three-paralogue background.
    evidence:
    - reference: PMID:33177972
      reference_title: In vivo Analysis of CRISPR/Cas9 Induced Atlastin Pathological Mutations in Drosophila.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Moreover, overexpression of the pathogenic variants in a wild type
        atlastin background does not give rise to the loss of function
        phenotypes expected for dominant negative mutations. These results
        indicate that the four pathological mutations investigated act through a
        loss of function mechanism.
      explanation: The fly evidence for a loss-of-function rather than dominant-negative mechanism of four patient variants.
  - target: Presynaptic Dysfunction of Corticospinal Neurons
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Motor-neuron atlastin loss depletes presynaptic terminals and disturbs
      synaptic vesicle pools, with progressive locomotor decline.
    limitations: >-
      Fly larval motor neurons are lower motor neurons at a neuromuscular
      junction, not corticospinal projection neurons, and the readout is
      locomotion rather than spasticity.
    readouts:
    - name: Adult climbing ability
      target: Presynaptic Dysfunction of Corticospinal Neurons
      direction: DECREASED
      interpretation: Progressive locomotor decline as the behavioural correlate of presynaptic failure.
      evidence:
      - reference: PMID:28860117
        reference_title: Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Using Drosophila, we demonstrate that downregulation or overexpression
          of Atlastin in motor neurons results in decreased crawling speed and
          contraction frequency in larvae, while adult flies show progressive
          decline in climbing ability.
        explanation: Reports the locomotor measurements behind this readout.
    evidence:
    - reference: PMID:28860117
      reference_title: Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Additionally, axonal secretory organelles are abnormally distributed,
        whereas presynaptic proteins diminish at terminals and accumulate in
        distal axons, possibly in lysosomes.
      explanation: The presynaptic depletion that makes the model informative for this node.
  - target: Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Flies carrying pure-HSP patient-variant homologues show disrupted lipid
      homeostasis in long motor nerves that is partially corrected by an LXR
      agonist, the same pharmacology that rescues the human stem-cell lipid
      phenotype.
    limitations: >-
      The fly lesion is lipid droplet accumulation within nerves, whereas the
      human astrocyte phenotype is smaller lipid droplets and failed cholesterol
      export; the direction differs and the fly has no astrocyte-to-neuron
      cholesterol shuttle of the human kind. The complex-variant flies show no
      lipid phenotype at all.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The fly quantity is lipid droplet accumulation in nerve; the node's
        quantity is astrocyte lipid-droplet size and cholesterol transfer to
        neurons. Shared LXR responsiveness, not a shared measurement, is what
        links them.
    readouts:
    - name: Lipid droplet accumulation in motor nerves (pure-variant models)
      target: Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons
      direction: INCREASED
      interpretation: Lipid homeostasis lesion in the pure-HSP fly models.
      evidence:
      - reference: PMID:42419637
        reference_title: Mutation-specific cellular mechanisms in Drosophila models of ATL1-associated hereditary spastic paraplegia.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Models of pure ATL1-HSP display disrupted lipid homeostasis, including
          lipid droplet accumulation within nerves comprising long motor neuron
          axons, which is partially ameliorated by treatment with a liver X
          receptor (LXR) agonist.
        explanation: Reports the lipid droplet measurement and the LXR rescue arm.
    evidence:
    - reference: PMID:42419637
      reference_title: Mutation-specific cellular mechanisms in Drosophila models of ATL1-associated hereditary spastic paraplegia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In contrast, complex ATL1-HSP Drosophila lack lipid droplet
        abnormalities and do not respond to LXR activation but instead show
        disruption of the neuronal endoplasmic reticulum, consistent with
        aberrant ER network regulation.
      explanation: >-
        Bounds the link: only the pure-variant models carry the lipid lesion,
        so the model is informative for this node for pure SPG3A alleles only.
  evidence:
  - reference: PMID:17030474
    reference_title: Loss of spastic paraplegia gene atlastin induces age-dependent death of dopaminergic neurons in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As they aged, atl null flies were paralyzed by mechanical shock such as
      bumping or vortexing. Furthermore, the flies showed age-dependent
      degeneration of dopaminergic neurons.
    explanation: >-
      The original atl null: a progressive, age-dependent neurological
      phenotype, but the dopaminergic neuron loss has no counterpart in SPG3A
      (see the model-mismatch discussion).
- name: Zebrafish atl1 morphant
  species: Danio rerio
  genotype: atl1 morpholino knockdown (and atl1 mRNA overexpression)
  description: >-
    Morpholino knockdown of atl1 in the developing zebrafish severely reduces
    larval mobility, preceded by abnormal spinal motor axon architecture and a
    substantial up-regulation of BMP signalling; atlastin overexpression
    inhibits BMP signalling, and genetic or pharmacological BMP inhibition
    rescues the morphant.
  publication: PMID:20935645
  modeled_mechanisms:
  - target: Dysregulated BMP Signalling from Impaired BMPRII Trafficking
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Establishes atlastin as a negative regulator of BMP signalling in
      vertebrate motor neurons and shows that BMP dysregulation is sufficient
      to disturb motor axon architecture.
    limitations: >-
      Knockdown raises BMP signalling, whereas patient dominant-negative
      variants blunt the BMP4 response in cells; the model is developmental,
      and zebrafish have no corticospinal tract.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Zebrafish lack a corticospinal tract, so the motor axons examined are
        spinal motor axons rather than the long central axons that degenerate
        in patients.
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model quantity is total BMP pathway output after atlastin
        knockdown, which rises; the node's quantity is BMPRII surface
        trafficking and the BMP4 response under a dominant-negative patient
        variant, which fall. The model shows that atlastin gates BMP signalling
        in motor axons, not the trafficking step or its direction in patients.
    readouts:
    - name: BMP pathway activity in atl1 morphants
      target: Dysregulated BMP Signalling from Impaired BMPRII Trafficking
      direction: INCREASED
      interpretation: Direction of BMP change on atlastin loss in vivo.
      evidence:
      - reference: PMID:20935645
        reference_title: Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Overexpression analyses confirmed that atlastin inhibits BMP
          signaling.
        explanation: Reports the gain-of-function confirmation that atlastin inhibits BMP signalling.
    - name: Larval mobility after BMP inhibition
      target: Dysregulated BMP Signalling from Impaired BMPRII Trafficking
      direction: RESTORED
      interpretation: Rescue arm establishing causality of the BMP change for the motor phenotype.
      evidence:
      - reference: PMID:20935645
        reference_title: Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Finally, genetic or pharmacological inhibition of BMP signaling was
          sufficient to rescue the loss of mobility and spinal motor axon
          defects of atl1 morphants
        explanation: Reports the rescue measurement behind this readout.
    evidence:
    - reference: PMID:20935645
      reference_title: Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We found that knockdown of the gene for atlastin (atl1) caused a severe
        decrease in larval mobility that was preceded by abnormal architecture
        of spinal motor axons and was associated with a substantial upregulation
        of the bone morphogenetic protein (BMP) signaling pathway.
      explanation: The morphant phenotype that makes the model informative for the BMP node.
- name: C. elegans atln-1 mutant
  species: Caenorhabditis elegans
  genotype: atln-1 GTPase-impaired mutants and knock-in of patient ATL1 alleles
  description: >-
    In the PVD sensory neuron, atln-1 mutants with impaired GTPase activity
    lose the ER networks of the soma and dendrite branch points, ER tubules
    retract from higher-order dendrites, microtubules there are destabilised
    and mitochondrial fission at branch points fails; patient alleles reproduce
    the ER phenotype.
  publication: PMID:30718476
  modeled_mechanisms:
  - target: Disrupted Tubular ER Network in Neurons
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: In vivo neuronal ER morphology under atlastin loss, with patient alleles tested.
    limitations: >-
      A dendritic ER phenotype in an invertebrate sensory neuron; the human
      lesion is axonal, in a corticospinal projection neuron.
    readouts:
    - name: ER network at soma and dendrite branch points
      target: Disrupted Tubular ER Network in Neurons
      direction: DECREASED
      interpretation: Loss of network ER, replaced by tubules, on GTPase impairment.
      evidence:
      - reference: PMID:30718476
        reference_title: Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In atln-1 mutants with impaired GTPase activity, ER networks in soma
          and dendrite branch points are reduced and replaced by tubules, and ER
          tubules retracted from high-order dendritic branches, causing
          destabilized microtubule in these branches.
        explanation: Reports the ER morphology measurement behind this readout.
    evidence:
    - reference: PMID:30718476
      reference_title: Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mutant alleles of Atlastin-1 found in Hereditary Spastic Paraplegia
        (HSP) patients show similar ER phenotypes, suggesting that neuronal ER
        impairment contributes to HSP disease pathogenesis.
      explanation: Patient alleles reproduce the phenotype, which is what makes the worm informative for SPG3A.
experimental_models:
- name: SPG3A patient iPSC-derived forebrain neurons (ATL1 p.Pro342Ser)
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Induced pluripotent stem cells from the skin fibroblasts of a girl with
    pure SPG3A carrying p.Pro342Ser, differentiated into forebrain neurons: the
    first human neuronal model of SPG3A.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: patient dermal fibroblast-derived iPSC
  publication: PMID:24908668
  modeled_mechanisms:
  - target: Impaired Axonal ER Distribution, Organelle Transport and Axon Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Patient neurons show impaired axon growth and altered mitochondrial
      motility, and the growth defect is rescued by microtubule-binding agents.
    limitations: >-
      Immature cultured neurons with short axons cannot report the
      length-dependent degeneration of a metre-long corticospinal axon; a single
      patient line without an isogenic control.
    readouts:
    - name: Axon growth
      target: Impaired Axonal ER Distribution, Organelle Transport and Axon Growth
      direction: DECREASED
      interpretation: The axon-growth defect of SPG3A neurons.
      evidence:
      - reference: PMID:24908668
        reference_title: Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Axons of these SPG3A neurons showed impaired growth, recapitulating
          axonal defects in atlastin-1-depleted rat cortical neurons and impaired
          root hair growth in loss-of-function mutants of the ATL1 ortholog rhd3
          in the plant Arabidopsis.
        explanation: Reports the axon growth measurement.
    - name: Axon growth after microtubule-binding agents
      target: Impaired Axonal ER Distribution, Organelle Transport and Axon Growth
      direction: RESTORED
      interpretation: Pharmacological rescue arm.
      evidence:
      - reference: PMID:24908668
        reference_title: Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          The SPG3A axon growth defects could be rescued with
          microtubule-binding agents, emphasizing the importance of tubular ER
          interactions with the microtubule cytoskeleton in hereditary spastic
          paraplegia pathogenesis.
        explanation: Reports the rescue measurement.
    evidence:
    - reference: PMID:24908668
      reference_title: Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We produced induced pluripotent stem cells from skin fibroblasts and
        differentiated these into forebrain neurons to generate a human neuronal
        model for SPG3A.
      explanation: Describes the model as a human neuronal model for SPG3A.
- name: Isogenic hPSC ATL1 A161P and patient P342S cortical projection neurons with astrocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Isogenic human pluripotent stem cell lines carrying ATL1 A161P, and the
    P342S patient line, differentiated into cortical projection neurons and
    astrocytes, with neuron-astrocyte co-culture and conditioned-medium
    experiments.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  publication: PMID:33287888
  modeled_mechanisms:
  - target: Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The model in which the astrocyte lipid-droplet and cholesterol-transfer
      defect was discovered and rescued.
    limitations: >-
      In vitro co-culture cannot show that glial cholesterol supply limits
      corticospinal axon survival in the patient brain; no in vivo confirmation
      exists.
    readouts:
    - name: Astrocyte lipid droplet size
      target: Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons
      direction: DECREASED
      interpretation: The glial lipid-droplet defect.
      evidence:
      - reference: PMID:33287888
        reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Importantly, ATL1 mutations dysregulated proteolipid gene expression,
          reduced lipid droplet size in astrocytes, and unexpectedly disrupted
          cholesterol transfer from glia to neurons, leading to cholesterol
          deficiency in SPG3A cortical PNs.
        explanation: Reports the lipid-droplet and cholesterol-transfer measurements.
    - name: Axonal transport and swellings after cholesterol or control-astrocyte medium
      target: Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons
      direction: RESTORED
      interpretation: Rescue arm establishing the glial cholesterol deficit as causal for the neuronal phenotype.
      evidence:
      - reference: PMID:33287888
        reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Applying cholesterol or conditioned medium from control astrocytes, a
          major source of cholesterol in the brain, rescued aberrant axonal
          transport and swellings in SPG3A cortical PNs.
        explanation: Reports the rescue measurement.
    - name: Astrocyte lipid droplets, cholesterol efflux and neuronal axonal degeneration after GW3965
      target: Impaired Astrocyte Lipid Droplet Formation and Cholesterol Supply to Neurons
      direction: RESTORED
      interpretation: A second, pharmacological rescue arm acting on the astrocyte through LXR.
      evidence:
      - reference: PMID:33287888
        reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Furthermore, treatment with the NR1H2 agonist GW3965 corrected lipid
          droplet defects in SPG3A astrocytes and promoted cholesterol efflux
          from astrocytes, leading to restoration of cholesterol levels and
          rescue of axonal degeneration in SPG3A cortical PNs.
        explanation: Reports the LXR-agonist rescue measurements.
    evidence:
    - reference: PMID:33287888
      reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We generated isogenic human pluripotent stem cell (hPSC) lines for two
        ATL1 missense mutations associated with SPG3A, the most common
        early-onset autosomal dominant HSP.
      explanation: Describes the isogenic lines behind the model.
  - target: Impaired Axonal ER Distribution, Organelle Transport and Axon Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Reduced axonal outgrowth, impaired axonal transport and axonal swellings in cortical projection neurons.
    limitations: Cultured neurons cannot report length-dependent degeneration of a corticospinal axon in vivo.
    evidence:
    - reference: PMID:33287888
      reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In hPSC-derived cortical PNs, ATL1 mutations resulted in reduced axonal
        outgrowth, impaired axonal transport, and accumulated axonal swellings,
        recapitulating disease-specific phenotypes.
      explanation: The axonal phenotypes that make the model informative for the transport node.
- name: SPG3A patient iPSC-derived cortical projection neurons (P342S and M408T)
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Cortical projection neurons differentiated from iPSCs of two SPG3A
    patients with distinct missense variants, profiled by RNA sequencing and
    calcium imaging and treated with the orally bioavailable LXR agonist
    LXR623.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:41250225
  modeled_mechanisms:
  - target: Presynaptic Dysfunction of Corticospinal Neurons
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Synaptic gene and protein loss and reduced calcium activity in patient
      neurons from two variants, rescued by an LXR agonist.
    limitations: >-
      Cultured cortical neurons without their spinal targets; synaptic
      dysfunction and apoptosis in a dish may not correspond to the dying-back
      axonopathy without neuronal loss that characterises human HSP.
    readouts:
    - name: Synaptic gene and protein expression
      target: Presynaptic Dysfunction of Corticospinal Neurons
      direction: DECREASED
      interpretation: The synaptic dysfunction signature.
      evidence:
      - reference: PMID:41250225
        reference_title: LXR agonist rescues synaptic dysfunction and degeneration in SPG3A patient-specific iPSC-derived neurons.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          We observed significant reductions of synaptic genes and proteins in
          cortical PNs from both SPG3A-P342S and SPG3A-M408T patient iPSCs,
          emphasizing synaptic dysfunction in SPG3A neurons.
        explanation: Reports the synaptic measurements.
    - name: Synaptic proteins and calcium activity after LXR623
      target: Presynaptic Dysfunction of Corticospinal Neurons
      direction: RESTORED
      interpretation: Pharmacological rescue arm through lipid metabolism.
      evidence:
      - reference: PMID:41250225
        reference_title: LXR agonist rescues synaptic dysfunction and degeneration in SPG3A patient-specific iPSC-derived neurons.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          LXR623 significantly mitigated the reduction in synaptic proteins and
          calcium activity and rescued axonal degeneration and apoptosis in
          SPG3A cortical PNs.
        explanation: Reports the rescue measurement.
    evidence:
    - reference: PMID:41250225
      reference_title: LXR agonist rescues synaptic dysfunction and degeneration in SPG3A patient-specific iPSC-derived neurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, by comparing SPG3A patient iPSC-derived neurons with control cells
        using RNA-sequencing, we identified synaptic dysfunction as a
        top-altered pathway in addition to lipid-related pathways.
      explanation: The transcriptomic finding that makes the model informative for the synaptic node.
- name: Autologous iPSC-derived lower motor neuron and myotube neuromuscular junction co-culture
  experimental_model_type: CO_CULTURE
  description: >-
    Microfluidic co-cultures of lower motor neurons and myotubes differentiated
    from the same patient iPSC line, from three SPG3A and two SPG4 patients,
    used to model neuromuscular junction formation with the patient genotype in
    both cell types.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: lower motor neuron
    term:
      id: CL:0008039
      label: lower motor neuron
  culture_system: microfluidic compartmentalised neuron-muscle co-culture
  publication: PMID:36359747
  modeled_mechanisms:
  - target: Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Patient lower motor neurons show axonal swellings and form fewer, less
      complex neuromuscular junctions, a correlate of the lower motor neuron
      arm of the complicated form.
    limitations: >-
      The SPG3A and SPG4 lines were pooled in the reported readouts, so no
      finding is uniquely SPG3A; an in vitro junction is not a degenerating
      peripheral nerve.
    readouts:
    - name: Neuromuscular junction number and contact complexity
      target: Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves
      direction: DECREASED
      interpretation: Impaired NMJ profile of HSP patient-derived motor neurons.
      evidence:
      - reference: PMID:36359747
        reference_title: Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Furthermore, NMJs from HSP-derived lines were lower in number and in
          contact point complexity, denoting an impaired NMJ profile
        explanation: Reports the NMJ measurement (pooled SPG3A and SPG4 lines).
    - name: Axonal swellings with acetylated alpha-tubulin accumulation in lower motor neurons
      target: Distal Axonal Degeneration of Peripheral Motor and Sensory Nerves
      direction: INCREASED
      interpretation: The axonal pathology hallmark reproduced in patient-derived lower motor neurons.
      evidence:
      - reference: PMID:36359747
        reference_title: Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Differentiation of the HSP-derived lines gave rise to lower MNs that
          could recapitulate pathological hallmarks, such as axonal swellings
          with accumulation of Acetyl-α-TUBULIN and reduction of SPASTIN levels.
        explanation: Reports the axonal swelling measurement (pooled SPG3A and SPG4 lines).
    evidence:
    - reference: PMID:36359747
      reference_title: Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Three patients characterized by a mutation in the SPG3a gene, encoding
        the ATLASTIN GTPase 1 protein, and two patients with a mutation in the
        SPG4 gene, encoding the SPASTIN protein, were included in this study.
      explanation: Establishes that SPG3A patient lines are among those modelled.
discussions:
- discussion_id: controversy_atl1_dominant_negative_vs_loss_of_function
  prompt: >-
    Do SPG3A missense variants cause disease by a dominant-negative effect on
    atlastin-1 oligomers, by simple loss of function with dosage sensitivity,
    or by allele-specific mechanisms that differ between variants?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#ATL1 Variant Impairing the Atlastin-1 GTPase Cycle
  - genetic#ATL1
  rationale: >-
    Dominant inheritance with a missense-dominated spectrum, mixed-oligomer
    formation, and dominant-negative disruption of ER reticularisation and
    BMPRII trafficking in cells support a dominant-negative mechanism. Against
    it, four patient variants knocked into the endogenous fly gene behave as
    loss-of-function alleles that do not act as dominant negatives when
    overexpressed, the most frequently identified variant retains wild-type
    activity in every assay, one GTPase-domain variant is active while
    transmembrane variants vary, and homozygous families with asymptomatic
    heterozygous parents show that ATL1 can also cause recessive, dosage-type
    disease. The entry records DOMINANT_NEGATIVE as the best-supported
    category for the typical heterozygous allele but does not treat the
    question as settled.
  proposed_experiments:
  - experiment_id: exp_atl1_heterozygous_patient_variant_knockin_mouse
    name: Heterozygous patient-variant knock-in mice with corticospinal ER ultrastructure
    description: >-
      Generate mice heterozygous for frequent human alleles (R239C, R217Q,
      P342S) on a wild-type Reep1 background, age them, and compare
      corticospinal axonal ER by FIB-SEM and motor phenotype with heterozygous
      null and homozygous knock-in littermates. A phenotype in heterozygous
      missense but not heterozygous null animals would support a
      dominant-negative mechanism; equivalent phenotypes would support dosage.
    would_support:
    - pathophysiology#ATL1 Variant Impairing the Atlastin-1 GTPase Cycle
    supporting_outcome:
    - >-
      Heterozygous missense knock-in mice develop a corticospinal ER lesion and
      motor decline that heterozygous null mice do not.
    refuting_outcome:
    - >-
      Heterozygous missense and heterozygous null mice are indistinguishable,
      or neither shows a phenotype without Reep1 loss.
  evidence:
  - reference: PMID:16537571
    reference_title: SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we demonstrate that several missense SPG3A mutant atlastin-1
      proteins have impaired GTPase activity and thus may act in a
      dominant-negative, loss-of-function manner by forming mixed oligomers with
      wild-type atlastin-1.
    explanation: The dominant-negative side.
  - reference: PMID:33177972
    reference_title: In vivo Analysis of CRISPR/Cas9 Induced Atlastin Pathological Mutations in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results indicate that the four pathological mutations investigated
      act through a loss of function mechanism.
    explanation: The loss-of-function side, from patient variants in the endogenous fly gene.
  - reference: PMID:19573020
    reference_title: "Atlastin-1, the dynamin-like GTPase responsible for spastic paraplegia SPG3A, remodels lipid membranes and may form tubules and vesicles in the endoplasmic reticulum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The GTPase mutations T162P and R217C decreased but did not totally prevent
      this action; the C-terminal transmembrane domain mutation R495W was as
      active as the wild-type enzyme.
    explanation: >-
      Allele-specific heterogeneity: GTPase-domain variants partially impair membrane remodelling while a transmembrane variant is fully active.
  - reference: PMID:24473461
    reference_title: Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our combined findings show that homozygosity for the ATL1 missense
      variant remains the only plausible cause of HSP, whereas heterozygous
      carriers are asymptomatic.
    explanation: A recessive family, which a purely dominant-negative model does not predict.
  - reference: PMID:42419637
    reference_title: Mutation-specific cellular mechanisms in Drosophila models of ATL1-associated hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, these findings suggest that different mutations in Atl give
      rise to distinct cellular perturbations, suggesting a potential basis for
      phenotypic heterogeneity in ATL1-HSP.
    explanation: The allele-specific side, from fly models of pure versus complex patient variants.
- discussion_id: gap_atl1_axonal_er_status_in_patient_corticospinal_neurons
  prompt: >-
    What does the tubular ER of a human SPG3A corticospinal axon actually look
    like, and which downstream consequence of its disruption is the one that
    kills the distal axon?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Disrupted Tubular ER Network in Neurons
  - pathophysiology#Impaired Axonal ER Distribution, Organelle Transport and Axon Growth
  - pathophysiology#Distal Length-Dependent Corticospinal Axon Degeneration
  rationale: >-
    Every observation of the ER lesion comes from non-neuronal cells, cultured
    neurons with short axons, invertebrate neurons or the double-mutant mouse,
    where the axonal ER expands rather than fragments. No post-mortem
    ultrastructural study of SPG3A corticospinal axons exists, and the entry's
    edges from the ER network defect to distal degeneration are therefore
    inferred. Candidate intermediates that have each been shown in some system
    (ER-microtubule coupling, mitochondrial distribution, store-operated
    calcium entry, cholesterol supply, synaptic maintenance) have not been
    ranked against one another in a long human axon.
  proposed_experiments:
  - experiment_id: exp_spg3a_postmortem_corticospinal_er_ultrastructure
    name: Volume electron microscopy of SPG3A post-mortem corticospinal tract
    description: >-
      Serial-section or FIB-SEM reconstruction of thoracic corticospinal axons
      from SPG3A donors compared with age-matched controls and SPG4 donors,
      scoring axonal ER continuity, transverse expansion, three-way junction
      density and mitochondrial morphology along the axon.
    would_support:
    - pathophysiology#Disrupted Tubular ER Network in Neurons
    supporting_outcome:
    - >-
      SPG3A corticospinal axons show fragmented or transversely expanded ER
      with associated mitochondrial change, absent in controls.
    refuting_outcome:
    - >-
      Axonal ER morphology in SPG3A donors is indistinguishable from controls.
  evidence:
  - reference: PMID:33287888
    reference_title: Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hereditary spastic paraplegias (HSPs) are caused by a length-dependent
      axonopathy of long corticospinal neurons, but how axons of these cortical
      projection neurons (PNs) degenerate remains elusive.
    explanation: The authors' own statement of the gap this discussion records.
- discussion_id: mismatch_atl1_rodent_and_fly_models
  prompt: >-
    Why do single-gene atlastin-1 loss-of-function animals not reproduce the
    human early-onset corticospinal syndrome, and how should the fly's
    dopaminergic neuron loss and the mouse's requirement for Reep1 loss be
    weighed when using these models for therapy testing?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Mus musculus
  - animal_models#Drosophila melanogaster
  - pathophysiology#Distal Length-Dependent Corticospinal Axon Degeneration
  rationale: >-
    Mouse HSP models are typically mild and late-onset, plausibly because
    murine corticospinal axons are far shorter than human ones; a robust motor
    phenotype required combining a homozygous GTPase-dead Atl1 knock-in with
    Reep1 loss, a genotype no patient carries. The fly atl null degenerates
    dopaminergic neurons and becomes paralysed by mechanical shock, neither of
    which is part of SPG3A, and fly motor neurons are lower motor neurons. Both
    systems are therefore informative for the ER and transport nodes and much
    weaker for the corticospinal degeneration and spasticity nodes, and a
    rescue in either should not be read as evidence about the human axon
    without a length-dependent readout.
  proposed_experiments:
  - experiment_id: exp_atl1_length_dependent_readout_in_long_axon_systems
    name: Length-dependent readouts in long-axon human systems
    description: >-
      Use compartmentalised microfluidic cultures or engineered long-axon
      organoid-spinal assembloids from SPG3A patient and isogenic lines to
      measure ER continuity, organelle transport and degeneration as a function
      of distance from the soma, so that candidate therapies (microtubule
      stabilisers, LXR agonists, BMP modulators) are tested against a
      length-dependent phenotype rather than a short-axon growth assay.
    would_support:
    - pathophysiology#Distal Length-Dependent Corticospinal Axon Degeneration
    supporting_outcome:
    - >-
      Degeneration and transport failure increase with axon length in SPG3A
      lines and are corrected by the candidate therapy along the whole axon.
    refuting_outcome:
    - >-
      Phenotypes are length-independent or absent in long-axon human systems.
  evidence:
  - reference: PMID:35348668
    reference_title: Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Typically, mouse models of HSPs have mild, later onset phenotypes,
      possibly reflecting far shorter lengths of their corticospinal axons
      relative to humans.
    explanation: The mouse authors' own account of why single-gene rodent HSP models are mild.
  - reference: PMID:17030474
    reference_title: Loss of spastic paraplegia gene atlastin induces age-dependent death of dopaminergic neurons in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, the flies showed age-dependent degeneration of dopaminergic
      neurons.
    explanation: The fly phenotype with no human counterpart.
- discussion_id: question_atl1_penetrance_and_modifiers
  prompt: >-
    What determines the incomplete penetrance and the wide intrafamilial
    variability in onset of SPG3A, and are the genetic modifiers found in the
    fly relevant to patients?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - inheritance#Autosomal dominant
  - genetic#ATL1
  rationale: >-
    Asymptomatic carriers are recorded in French, Dutch-German and Russian
    series, one family with R495W ranged in onset from 8 to 28 years, and the
    de novo cluster shows that variant position explains part but not all of
    the severity range. A deficiency screen in the fly identified 35 enhancer
    and four suppressor regions of the atlastin-knockdown climbing phenotype
    and a genetic interaction with a Polycomb repressive complex 1 component,
    suggesting epigenetic modifiers, but no human modifier has been
    identified. Reduced and sex-dependent penetrance at a mutational hotspot
    (c.1243C>T and c.1244G>A) made two large ATL1 families look recessive or
    X-linked, so misread pedigrees are one reason SPG3A is under-ascertained.
  evidence:
  - reference: PMID:23483706
    reference_title: "Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A set of genetic analyses including exome sequencing revealed plausible
      mutations only when assuming incomplete/sex-dependent penetrance of
      adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T
      and c.1244G>A, respectively).
    explanation: Reduced and sex-dependent penetrance at an ATL1 hotspot disguising dominant inheritance.
  - reference: PMID:17502470
    reference_title: Hereditary spastic paraplegia 3A associated with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found incomplete penetrance in 1 family (G482V).
    explanation: Incomplete penetrance in the 182-family cohort.
  - reference: PMID:37368047
    reference_title: Identification of atlastin genetic modifiers in a model of hereditary spastic paraplegia in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that atl interacts genetically with Su(z)2, a component of the
      Polycomb repressive complex 1, suggesting that epigenetic regulation plays
      a role in the variability of HSP-like phenotypes caused by atl alleles.
    explanation: The fly modifier screen's lead candidate class.
references:
- reference: PMID:20862796
  title: Spastic Paraplegia 3A.
  tags:
  - GeneReviews
notes: >-
  Lump/split. The umbrella Hereditary_Spastic_Paraplegia entry already carries
  SPG3A as a has_subtypes row and one pathophysiology node for the atlastin-1
  ER-shaping defect. This dedicated entry follows the pattern set by the SPG7,
  SPG11, SPG44, SPG46, SPG48 and SPG49 entries and holds what the umbrella
  cannot: the allele-specific GTPase-cycle biology, the BMP, lipid and synaptic
  arms, the three subtypes, the recessive families, and the model systems. The
  umbrella's SPG3A node and subtype row were kept, following SPG7 and SPG11
  rather than SPG44-49: the umbrella's own phenotype rows carry `subtype:
  SPG3A`, so the row is a foreign-key target there and deleting it would break
  the umbrella, whereas the SPG44-49 rows had no dependants when they were
  removed. The allelic disorder HSN1D is a separate entry and is
  cross-referenced as a differential.


  Module conformance. The corticospinal chain conforms to
  corticospinal_tract_axonopathy at its trigger, transport, degeneration,
  disinhibition and spasticity nodes; the peripheral arm of the complicated
  form conforms to peripheral_axonal_degeneration at its axonal-degeneration
  node, as the module's own notes ask for complicated HSPs. The BMP, astrocyte
  cholesterol and synaptic nodes are SPG3A-specific and conform to nothing.


  Evidence choices. Human evidence establishes the gene, the phenotype, the
  subtypes and the neuropathy; the mechanism from GTPase cycle to fusion to ER
  network is IN_VITRO and structural, and everything from the ER lesion to the
  distal axon is inferred or from models, which the causal_link_type values and
  the knowledge-gap discussion say explicitly. The two hyperreflexia and
  Babinski items quote a general-HSP sentence from the full text of a review and
  are marked directness INDIRECT and evidence_source OTHER for that reason; the
  DeLuca post-mortem series is genotype-unspecified HSP and is marked INDIRECT
  as well. The prevalence record carries
  no rate because SPG3A's prevalence has only ever been derived from its share
  of dominant HSP.


  Left out deliberately. The early reports that atlastin-1 variants disrupt
  ER-to-Golgi vesicle trafficking (Namekawa 2007) were contradicted by two
  later studies that found anterograde trafficking normal, so no Golgi node was
  curated. Atlastin's roles in ER-phagy and in lunapark-dependent junction
  formation are not yet tied to any SPG3A variant. The LXR agonists and
  microtubule-binding agents are recorded as model rescues, not as treatments.
  The falcon report's Russian-journal cohort (Rudenskaya 2020) has no PubMed
  record and was not cited; its companion Scientific Reports paper was.

📚

References & Deep Research

References

1

PMID:20862796

Spastic Paraplegia 3A.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸

Hereditary Spastic Paraplegia 3A (SPG3A): Disease-Characteristics Report

Edison Scientific Literature 61 citations 2026-09-12T16:41:02.140791

Hereditary Spastic Paraplegia 3A (SPG3A): Disease-Characteristics Report

Scope. This report summarizes evidence available through 2024, prioritizing disease-specific human studies and distinguishing them from general hereditary spastic paraplegia (HSP) guidance and preclinical findings. Database identifiers should be revalidated against the release used by the target knowledge base. PMIDs are included only where verified in the retrieved evidence; DOI links are supplied otherwise.

Executive summary

SPG3A is a rare Mendelian upper-motor-neuron disorder caused by pathogenic variants in ATL1, which encodes the endoplasmic-reticulum (ER) membrane fusogen atlastin-1. The usual phenotype is autosomal-dominant, childhood-onset “pure” HSP: bilateral lower-limb spasticity, hyperreflexia, extensor plantar responses, gait impairment, and variable weakness or urinary symptoms. Onset commonly occurs at 1–3 years, the reported mean is approximately 4.6 years, progression is usually slow, and most affected people remain ambulatory. In 2024, three exceptional cases expanded the spectrum to severe disease beginning before seven months and supported rare autosomal-recessive inheritance from biallelic ATL1 variants. (rudenskaya2020clinicalmolecularand pages 1-2, hamamiechaar2024patientswithcomplex pages 1-2, hamamiechaar2024patientswithcomplex pages 2-4)

The strongest mechanistic model is that mutation-specific impairment of GTP-dependent ATL1-mediated ER membrane fusion disturbs the continuous tubular ER network in long axons. Downstream defects include abnormal axon growth, transport, and swellings. Human stem-cell work additionally implicates defective astrocyte lipid-droplet biology and astrocyte-to-neuron cholesterol transfer. However, a universal dominant-negative mechanism has not been established; loss-of-function, dominant-negative, dosage-dependent, and variant-specific effects may coexist. (mou2020impairedlipidmetabolism pages 1-2, sonda2021ermorphologyin pages 5-6, crosby2021reconstitutionofhuman pages 1-2)

There is no approved disease-modifying therapy or SPG3A-specific treatment trial. Current care is multidisciplinary and symptomatic. (maccora2024nonpharmacologicaltreatmentof pages 1-2, bellofatto2019managementofhereditary pages 1-2)

Domain	Finding	Evidence type	Source/date/DOI
2024 phenotypic expansion	Three unrelated individuals had severe onset before 7 months with axial hypotonia, spastic quadriplegia, dystonia, seizures, and intellectual disability. Variants were de novo heterozygous p.(Lys406Glu), homozygous p.(Arg403Glufs*3), and homozygous p.(Tyr367His); asymptomatic heterozygous parents in the latter two families support rare autosomal-recessive SPG3A. (hamamiechaar2024patientswithcomplex pages 1-2, hamamiechaar2024patientswithcomplex pages 2-4)	Human case series	Hamamie-Chaar et al.; July 2024; DOI: 10.1007/s00415-024-12565-0
Clinical frequency and penetrance	In Russia, SPG3A comprised 7.2% of 195 HSP families, 13.6% of 103 molecularly resolved families, and 16.9% of dominant forms. Among 14 SPG3A families, incomplete penetrance or subclinical disease occurred in five; 3 of 6 electrophysiologically tested patients had subclinical axonal polyneuropathy. (rudenskaya2020clinicalmolecularand pages 1-2)	Human cohort	Rudenskaya et al.; March 2020; DOI: 10.25692/acen.2020.1.5
Variant spectrum	In 122 Russian HSP probands, ATL1-related disease was found in 10 (8.2%), all familial. All ten variants were missense; most occurred in hotspot exons 4, 7, 8, and 12, and two were novel. (kadnikova2019mutationalspectrumof pages 1-2)	Human molecular cohort	Kadnikova et al.; October 2019; DOI: 10.1038/s41598-019-50911-9
Classic epidemiology and course	SPG3A represents approximately 10%–15% of dominant uncomplicated HSP and more than 75% of early-onset dominant cases. Typical onset is in the first decade—often age 1–3 years, with a reported mean of 4.6 years—and progression is generally slow with preserved ambulation; cerebral palsy is a recurrent initial misdiagnosis. (rudenskaya2020clinicalmolecularand pages 1-2, hamamiechaar2024patientswithcomplex pages 1-2, bick1993uncomplicated(pure)hereditary pages 1-3)	Aggregated human clinical evidence	GeneReviews-derived overview; Rudenskaya et al. 2020; Hamamie-Chaar et al. 2024
Causal gene and ER fusion	ATL1 encodes neuronally enriched atlastin-1, an ER-membrane dynamin-like GTPase. GTP-dependent dimerization, three-helix-bundle crossover, and amphipathic-helix insertion drive homotypic ER-membrane fusion; purified human ATL1 directly catalyzes GTP-dependent lipid mixing. The relative contributions of loss of function, dominant-negative action, and other mutation-specific effects remain unresolved. (sonda2021ermorphologyin pages 5-6, crosby2021reconstitutionofhuman pages 1-2)	Biochemical, structural, and cellular evidence	Crosby et al.; November 2021; DOI: 10.1083/jcb.202107070; Sonda et al.; October 2021; DOI: 10.3390/cells10112870
Astrocyte–neuron lipid mechanism	Isogenic ATL1-A161P and patient-derived ATL1-P342S models showed impaired axonal outgrowth and transport and axonal swellings. ATL1-mutant astrocytes had smaller lipid droplets and defective cholesterol transfer, causing neuronal cholesterol deficiency; cholesterol, control-conditioned medium, or the NR1H2/LXR agonist GW3965 rescued axonal abnormalities. (mou2020impairedlipidmetabolism pages 1-2)	Human hPSC/iPSC-derived cortical neurons and astrocytes; experimental rescue	Mou et al.; December 2020; DOI: 10.1186/s40478-020-01088-0
Neuromuscular-junction model	Autologous iPSC-derived lower-motor-neuron and myotube cultures from three SPG3A and two SPG4 patients produced fewer, less-complex neuromuscular junctions; HSP neurons showed axonal swellings and acetylated α-tubulin accumulation. Findings are preclinical and were not separately quantified for SPG3A in the cited summary. (costamagna2022autologousipscderivedhuman pages 1-2)	Human patient-derived iPSC microfluidic model	Costamagna et al.; 24 October 2022; DOI: 10.3390/cells11213351
Current treatment	No therapy is proven to halt, reverse, or prevent SPG3A progression. Current HSP care is individualized and symptomatic: physiotherapy, stretching, orthoses, mobility aids, oral baclofen, tizanidine or dantrolene, focal botulinum toxin, intrathecal baclofen for severe refractory spasticity, and bladder-directed therapy such as oxybutynin. Evidence is predominantly general HSP evidence rather than SPG3A-specific trials. (maccora2024nonpharmacologicaltreatmentof pages 1-2, bellofatto2019managementofhereditary pages 1-2, toft2017clinicalandgenetic pages 6-8)	Systematic reviews and clinical-management evidence	Maccora et al.; online 16 November 2023 / 2024 issue; DOI: 10.1007/s10072-023-07200-1; Bellofatto et al.; 22 January 2019; DOI: 10.3389/fneur.2019.00003

Table: Highest-value clinical, genetic, mechanistic, model-system, and treatment evidence for ATL1-related hereditary spastic paraplegia 3A. The table distinguishes human observations from preclinical findings and flags the absence of disease-modifying therapy.

1. Disease information

Definition and nomenclature

SPG3A is a genetic neurodevelopmental/neurodegenerative disorder in which length-dependent dysfunction and degeneration of corticospinal upper-motor-neuron axons produces progressive or relatively static spastic paraparesis. It is also called spastic paraplegia type 3A, ATL1-related hereditary spastic paraplegia, autosomal-dominant spastic paraplegia type 3, and atlastin-1–related HSP. The “pure” designation means that corticospinal manifestations predominate; “complex” SPG3A includes additional neurologic findings such as neuropathy, dystonia, seizures, or intellectual disability. (denton2015modellinghereditaryspastic pages 13-17, hamamiechaar2024patientswithcomplex pages 1-2, bick1993uncomplicated(pure)hereditary pages 1-3)

Identifiers

MONDO: MONDO:0008437. Open Targets maps this disease to ATL1/ENSG00000198513 with five evidence records, including PMIDs 11685207, 21194679, 21336785, 22340599, and 23483706. (OpenTargets Search: Hereditary spastic paraplegia 3A-ATL1)
OMIM phenotype: 182600, Spastic paraplegia 3A, autosomal dominant.
Gene: ATL1; approved name atlastin GTPase 1; commonly cited OMIM gene entry 606439; Ensembl ENSG00000198513. (OpenTargets Search: Hereditary spastic paraplegia 3A-ATL1)
Orphanet: SPG3A is represented within rare hereditary spastic paraplegia resources; the exact ORPHA record should be release-validated before ingestion.
ICD-10-CM: G11.4, hereditary spastic paraplegia, a group-level rather than SPG3A-specific code.
ICD-11/MeSH/SNOMED CT: these generally represent HSP at the group level; no universally used SPG3A-specific billing code was established in the retrieved literature.

The evidence summarized here is aggregated disease-level evidence from cohorts, case series, reviews, databases, and experimental studies—not individual EHR data.

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

The primary cause is a germline pathogenic ATL1 variant. Most recognized disease is caused by a heterozygous variant and follows autosomal-dominant inheritance. De novo heterozygous variants occur. Rare homozygous missense or truncating variants have produced severe recessive presentations, although the size of this evidence base remains small. (khan2014evidenceforautosomal pages 5-5, rudenskaya2020clinicalmolecularand pages 1-2, hamamiechaar2024patientswithcomplex pages 1-2)

Genetic risk factors

A pathogenic allele, an affected parent, or a family history of early-onset spastic gait is the dominant risk factor. In one Russian series, all ten ATL1 diagnoses were familial; another series included a de novo case and incomplete/subclinical penetrance in five of 14 families. (rudenskaya2020clinicalmolecularand pages 1-2, kadnikova2019mutationalspectrumof pages 1-2)

Most reported variants are missense substitutions, enriched in exons 4, 7, 8, and 12 and affecting the GTPase or three-helix-bundle machinery. Nevertheless, deletions, insertions, splice variants, exon deletions, and frameshift variants are documented. (kadnikova2019mutationalspectrumof pages 1-2, sonda2021ermorphologyin pages 5-6)

Environmental and protective factors

No toxin, infection, diet, occupation, smoking exposure, or lifestyle factor is established as a cause of SPG3A. No validated protective human allele or environmental exposure is known. Exercise and rehabilitation preserve mobility and prevent secondary complications but have not been shown to prevent the molecular disease. Likewise, cholesterol supplementation and LXR activation are experimental cellular rescues, not proven protective interventions in humans. (mou2020impairedlipidmetabolism pages 1-2, maccora2024nonpharmacologicaltreatmentof pages 1-2)

No robust SPG3A gene–environment interaction has been demonstrated. Apparent variability is currently attributed primarily to variant-specific biology, penetrance, genetic background, age, and ascertainment.

3. Phenotypes

Core phenotype and suggested HPO annotations

Lower-limb spasticity—clinical sign, usually bilateral and symmetric; HP:0001257.
Spastic paraplegia/paraparesis—sign and functional manifestation; HP:0001278.
Lower-limb weakness—symptom/sign; HP:000腿 weakness concept should be mapped to the current HPO release, commonly represented as lower-limb muscle weakness.
Hyperreflexia—sign; HP:0001347.
Extensor plantar response/Babinski sign—sign; HP:0003487.
Abnormal/spastic or scissoring gait—sign; HP:0001288 and HP:0002066, subject to release validation.
Urinary urgency or bladder dysfunction—symptom; HP:0000012/more specific current term.
Distal sensory impairment or axonal polyneuropathy—laboratory/clinical sign; HP:0000763 and HP:0003477.

Classic SPG3A begins in the first decade, often at 1–3 years, and has a reported mean onset of 4.6 years. It is generally mild-to-moderate, pure, and slowly progressive, with preserved ambulation. Early-onset disease may plateau and resemble spastic diplegic cerebral palsy. (rudenskaya2020clinicalmolecularand pages 1-2, hamamiechaar2024patientswithcomplex pages 1-2, bick1993uncomplicated(pure)hereditary pages 1-3)

In the Russian clinical series, most of 25 examined patients had early-onset uncomplicated HSP with slow progression. Subclinical axonal polyneuropathy occurred in 3/6 electrophysiologically tested patients. (rudenskaya2020clinicalmolecularand pages 1-2)

Complex and exceptional phenotypes

Suggested terms include axial hypotonia (HP:0008936), spastic quadriplegia (HP:0002510), dystonia (HP:0001332), seizures (HP:0001250), intellectual disability (HP:0001249), global developmental delay (HP:0001263), dysarthria (HP:0001260), dysphagia (HP:0002015), delayed myelination (HP:0012448), and skeletal deformity/scoliosis (HP:0002650).

The 2024 report described three unrelated children with onset before seven months, early axial hypotonia followed by progressive limb spasticity, and severe complex disease. Features included tetraplegia, dystonia, seizures, intellectual disability, dysarthria, swallowing problems, and profound motor dependence. Two had initially been diagnosed with cerebral palsy. In the collaborating French databases, none of 96 previously confirmed ATL1 cases had comparably severe disease in the first year, underscoring its exceptional nature. (hamamiechaar2024patientswithcomplex pages 1-2, hamamiechaar2024patientswithcomplex pages 2-4)

Quality of life

Gait limitation, falls, fatigue, painful spasms, contractures, bladder symptoms, and dependence on mobility aids can impair education, employment, self-care, and participation. Formal SPG3A-specific EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life statistics were not identified. General HSP reviews conclude that lifespan is usually preserved while disability and quality-of-life impairment accumulate with severity. (awuah2024hereditaryspasticparaplegia pages 1-2, bick1993uncomplicated(pure)hereditary pages 1-3)

4. Genetic and molecular information

Gene and protein

ATL1 encodes atlastin-1, a neuronally enriched, integral ER-membrane dynamin-like GTPase. The protein contains an N-terminal GTPase domain, three-helix-bundle domain, two closely spaced transmembrane segments, and a C-terminal amphipathic region. It interacts functionally with other ER-shaping HSP proteins, including spastin, REEP1, and reticulon-2. (toft2017clinicalandgenetic pages 6-8, sonda2021ermorphologyin pages 5-6, crosby2021reconstitutionofhuman pages 1-2)

Suggested molecular annotations include GTPase activity (GO:0003924), GTP binding (GO:0005525), endoplasmic-reticulum membrane (GO:0005789), membrane fusion (GO:0061025), ER organization (GO:0007029), and homotypic membrane fusion using the most specific current GO term.

Variant spectrum and classification

Examples supported by human evidence include:

p.Arg415Trp: recurrent in four Russian families; incomplete penetrance has been observed for some recurrent ATL1 alleles. (rudenskaya2020clinicalmolecularand pages 1-2)
c.353G>A, p.Arg118Gln: homozygous missense change at a conserved GTPase-domain residue, proposed to cause recessive SPG3A. (khan2014evidenceforautosomal pages 5-5)
c.1216A>G, p.Lys406Glu: de novo heterozygous missense change in the three-helix-bundle region, associated with severe very-early-onset disease. (hamamiechaar2024patientswithcomplex pages 2-4)
c.1207del, p.Arg403Glufs*3: homozygous frameshift, with asymptomatic heterozygous parents. (hamamiechaar2024patientswithcomplex pages 1-2, hamamiechaar2024patientswithcomplex pages 2-4)
c.1099T>C, p.Tyr367His: homozygous missense variant, also with asymptomatic heterozygous parents. (hamamiechaar2024patientswithcomplex pages 1-2, hamamiechaar2024patientswithcomplex pages 2-4)

In 122 Russian HSP probands, ten had ATL1 diagnoses; all ten variants were missense, most in hotspot exons 4, 7, 8, or 12, and two were novel. A related 14-family analysis found nine missense variants, four novel. (rudenskaya2020clinicalmolecularand pages 1-2, kadnikova2019mutationalspectrumof pages 1-2)

Clinical classification must use current ClinVar submissions and ACMG/AMP criteria at the individual-variant level. Pathogenicity should not be inferred solely from rarity or an ATL1 location. Disease-causing variants are expected to be absent or extremely rare in population databases, but the retrieved evidence did not supply reliable allele frequencies for each variant. Variants are germline; no somatic ATL1 mechanism is established.

Functional consequence, modifiers, epigenetics, and structural variation

Many variants impair GTP binding/hydrolysis, oligomerization, membrane insertion, or fusion. A dominant-negative model is plausible because ATL1 functions as a dimer, but experiments have not supported one mechanism for all variants. Some behave as partial loss-of-function alleles, and dosage effects are evident in models. (sonda2021ermorphologyin pages 5-6, damiani2024pluripotentstemcells pages 3-3)

No clinically validated human modifier gene, epigenetic signature, methylation biomarker, anticipation mechanism, or recurrent pathogenic chromosomal rearrangement is established. ATL1 exon-level copy-number changes are possible but appear much less prominent than missense variants. Germline mosaicism is theoretically relevant to apparently de novo cases but was not quantified.

5. Environmental information

SPG3A is not infectious, toxic, nutritional, occupational, radiation-induced, or zoonotic. Environmental exposures do not presently form part of causal classification or risk stratification. Lifestyle management—regular activity, stretching, healthy weight, fall prevention, and avoidance of deconditioning—targets secondary disability rather than ATL1 pathogenesis. (maccora2024nonpharmacologicaltreatmentof pages 1-2, toft2017clinicalandgenetic pages 6-8)

6. Mechanism and pathophysiology

Ordered causal chain

A germline pathogenic ATL1 variant leads to mutation-specific alteration of atlastin-1 abundance, GTPase-cycle dynamics, dimerization, membrane engagement, or fusogenic activity.
Altered atlastin-1 leads to deficient or dysregulated GTP-dependent homotypic fusion of ER tubules and disturbed tubular-ER topology; this step is biochemically demonstrated for ATL1 function, but the magnitude and direction of dysfunction vary by allele. (sonda2021ermorphologyin pages 5-6, crosby2021reconstitutionofhuman pages 1-2)
Abnormal ER topology results in impaired maintenance of the continuous axonal ER network and perturbed interactions with microtubules, membrane trafficking, and organelle/lipid homeostasis; the direct disease-causal linkage remains partly inferred. (toft2017clinicalandgenetic pages 6-8, sonda2021ermorphologyin pages 5-6)
Neuron-autonomous branch: ER and cytoskeletal dysfunction leads to reduced axonal outgrowth, impaired axonal transport, axonal swellings, dendritic abnormalities, and synaptic/NMJ defects. (mou2020impairedlipidmetabolism pages 1-2, costamagna2022autologousipscderivedhuman pages 1-2, damiani2024pluripotentstemcells pages 2-3)
Glial branch: ATL1 dysfunction in astrocytes leads to altered proteolipid expression, smaller lipid droplets, and impaired cholesterol export; this results in cholesterol deficiency in cortical projection neurons. (mou2020impairedlipidmetabolism pages 1-2)
Convergent transport, trophic, membrane, and lipid defects lead to preferential dysfunction and distal degeneration of exceptionally long corticospinal axons; selective vulnerability is strongly supported, but the exact terminal injury pathway is inferred. (denton2015modellinghereditaryspastic pages 13-17, mou2020impairedlipidmetabolism pages 1-2)
Loss of descending corticospinal control results in bilateral lower-limb hyperreflexia, spasticity, weakness, Babinski signs, and gait impairment. (bick1993uncomplicated(pure)hereditary pages 1-3, meyyazhagan2022hereditaryspasticparaplegia pages 1-2)

Molecular detail and recent research

Single-molecule work published in March 2024 refined the atlastin cycle: GTP binding forms a loose crossover dimer, GTP hydrolysis tightens it to drive fusion, and phosphate release promotes disassembly and recycling. Two disease mutations impaired activity through distinct structural effects, supporting allele-specific mechanisms (DOI 10.1038/s41467-024-46919-z). The earlier human reconstitution study directly demonstrated GTP-dependent lipid mixing by purified ATL1 and identified C-terminal autoinhibition. (crosby2021reconstitutionofhuman pages 1-2)

An exact abstract statement from the reconstitution study is: “purified atlastin1 and atlastin2 are capable of fusion catalysis.” (crosby2021reconstitutionofhuman pages 1-2)

The most disease-specific multi-lineage profiling comes from human pluripotent-cell models. ATL1-A161P and patient-derived ATL1-P342S cortical neurons had reduced axonal growth, impaired transport, and swellings. Mutant astrocytes exhibited dysregulated proteolipid expression and smaller lipid droplets, with deficient cholesterol transfer to neurons. Cholesterol, control-astrocyte conditioned medium, and the NR1H2/LXR agonist GW3965 rescued cellular abnormalities. This is compelling preclinical evidence, not evidence of clinical efficacy. (mou2020impairedlipidmetabolism pages 1-2)

Suggested GO terms: ER organization (GO:0007029), membrane fusion (GO:0061025), axon development (GO:0061564), axonal transport (GO:0098930), cholesterol transport (GO:0030301), lipid-droplet organization (current GO release), neuron projection maintenance (GO:0031175), and synapse organization (GO:0050808). Suggested cell types are corticospinal neuron/upper motor neuron, cortical projection neuron (CL:0010012, release validation required), astrocyte (CL:0000127), lower motor neuron (CL:0000100), and skeletal-muscle cell (CL:0000188).

No validated SPG3A-specific immune, inflammatory, metabolomic, proteomic, epigenomic, single-cell, or spatial-transcriptomic signature has entered clinical use.

7. Anatomical structures affected

The primary system is the central nervous system, particularly bilateral long corticospinal tracts and their cortical projection neurons. Distal corticospinal axons in the thoracic spinal cord are especially vulnerable; demyelination, where present, is considered secondary to axonal injury. Peripheral axons may be subclinically involved. (denton2015modellinghereditaryspastic pages 13-17, rudenskaya2020clinicalmolecularand pages 1-2)

Suggested annotations include nervous system (UBERON:0001016), cerebral cortex (UBERON:0000956), spinal cord (UBERON:0002240), corticospinal tract (current UBERON/FMA mapping), thoracic spinal cord, lower limb (UBERON:0002103), skeletal muscle (UBERON:0001134), and neuromuscular junction (UBERON:0001015, release validation required).

Subcellular structures include tubular ER/ER membrane (GO:0005783/GO:0005789), axon (GO:0030424), growth cone (GO:0030426), microtubule cytoskeleton (GO:0015630), lipid droplet (GO:0005811), and synapse (GO:0045202). Disease is usually bilateral and symmetric rather than lateralized. (mou2020impairedlipidmetabolism pages 1-2, costamagna2022autologousipscderivedhuman pages 1-2)

8. Temporal development

Typical onset is insidious during infancy or childhood, usually before age ten and often at 1–3 years. Progression is slow and may become nearly static after an early developmental presentation. Adult onset is possible but uncommon. (rudenskaya2020clinicalmolecularand pages 1-2, bick1993uncomplicated(pure)hereditary pages 1-3)

There is no validated staging system. A practical functional description is: early toe walking/stiff gait; intermediate increasing spasticity, falls, contractures, or bladder symptoms; and advanced need for aids or wheelchair in severely affected individuals. Typical SPG3A patients often remain ambulatory, whereas the rare severe 2024 cases never achieved independent walking or retained only a few assisted steps. (hamamiechaar2024patientswithcomplex pages 1-2, hamamiechaar2024patientswithcomplex pages 2-4)

The disease is lifelong, with no true spontaneous remission. Childhood may be a critical intervention window because contracture prevention and gait preservation are easier before fixed deformities develop, but a molecular therapeutic window has not been defined.

9. Inheritance and population

Epidemiology

Reliable population prevalence and incidence specific to SPG3A are unavailable. General HSP prevalence is reported as 0.1–9.6 per 100,000; one review cited an overall incidence estimate of 3.6 per 100,000, but this is not SPG3A-specific. (awuah2024hereditaryspasticparaplegia pages 1-2, meyyazhagan2022hereditaryspasticparaplegia pages 1-2)

SPG3A has been estimated at 2–3% of all HSP, 8–10% of familial dominant HSP, approximately 10–15% of dominant uncomplicated HSP, and more than 75% of early-onset dominant uncomplicated HSP. Ascertainment and population differences explain part of the range. (kadnikova2019mutationalspectrumof pages 1-2, bick1993uncomplicated(pure)hereditary pages 1-3)

Recent cohort statistics include:

Russia: 10/122 (8.2%) HSP probands had ATL1 variants. (kadnikova2019mutationalspectrumof pages 1-2)
Expanded Russian analysis: 14/195 families (7.2%), 14/103 molecularly resolved families (13.6%), and 16.9% of dominant forms. (rudenskaya2020clinicalmolecularand pages 1-2)
A 1,550-index-case HSP panel cohort found ATL1 among genes accounting individually for more than 1% of all cases; the overall panel yield was 30.7%, not an SPG3A-specific yield.

Mendelian features

Classical inheritance is autosomal dominant, giving each child of a heterozygous affected individual a 50% transmission probability. Penetrance is high overall but incomplete and allele-/age-dependent; five of 14 Russian families contained subclinical carriers. Sex-dependent penetrance has been reported, but no stable male:female ratio is established. (khan2014evidenceforautosomal pages 5-5, rudenskaya2020clinicalmolecularand pages 1-2, toft2017clinicalandgenetic pages 6-8)

Rare autosomal-recessive SPG3A is supported by homozygous variants and unaffected heterozygous parents. Its frequency is unknown and evidence remains limited to small numbers of families. (khan2014evidenceforautosomal pages 5-5, hamamiechaar2024patientswithcomplex pages 1-2)

Expressivity is variable, including within families. Genetic anticipation is not established. Founder effects, carrier frequency, and effects of consanguinity have not been quantified globally. No ethnic group is intrinsically protected; cases occur worldwide.

10. Diagnostics

Clinical evaluation

Suspect SPG3A in a child with chronic, symmetric spastic gait, corticospinal signs, normal or near-normal cognition, and a dominant family history—particularly when labeled as cerebral palsy despite progression, affected relatives, or no perinatal insult. Fink-style HSP criteria emphasize progressive symmetric spastic gait, family history, corticospinal signs, and exclusion of alternative causes. (maccora2024nonpharmacologicaltreatmentof pages 1-2)

Neurologic examination should assess tone, strength, reflexes, plantar responses, gait, joint range, sensation, bladder function, cognition, speech/swallowing, dystonia, seizures, and family history. MRI brain and spine exclude structural, inflammatory, vascular, and demyelinating mimics; imaging is often normal in pure HSP. EMG/nerve-conduction studies are useful when neuropathy is suspected and may identify subclinical involvement. (rudenskaya2020clinicalmolecularand pages 1-2, toft2017clinicalandgenetic pages 6-8)

No blood, urine, enzyme, biopsy, pathology, or fluid biomarker is diagnostic. Neurofilament light and other neurodegeneration markers remain investigational and are not validated for SPG3A.

Genetic testing strategy

Use an NGS HSP/spastic-ataxia panel containing ATL1, SPAST, REEP1, KIF1A, KIF5A, SPG11, SPG7, and relevant mimics, with validated copy-number analysis.
Confirm reportable variants by an orthogonal method where required and test parents/relatives for segregation, de novo status, penetrance, or phase.
If negative, use exome or genome sequencing with CNV, splice, and reanalysis capability. A 1,550-case study supported panel-first testing and found that exome sequencing after a negative panel could raise theoretical yield toward 50% in a selected subset. General cohort evidence also shows that NGS can miss deep-intronic, regulatory, repeat, or structural lesions. (toft2017clinicalandgenetic pages 16-18)
Single-gene ATL1 sequencing is reasonable where the phenotype and pedigree are highly characteristic, but broad panels better address overlap.

CMA, karyotyping, and FISH are not first-line for isolated classic SPG3A. Mitochondrial DNA and repeat-expansion testing are phenotype-directed. RNA sequencing may help resolve suspected splice variants but is not routine. Population newborn screening is unavailable.

Differential diagnosis

Important alternatives include spastic diplegic cerebral palsy, SPG4 and other HSPs, multiple sclerosis, structural/compressive spinal disease, vitamin B12 deficiency, adrenomyeloneuropathy/ABCD1 disease, Friedreich ataxia, ARSACS, primary lateral sclerosis, dopa-responsive dystonia, leukodystrophy, and metabolic disease. (toft2017clinicalandgenetic pages 16-18, toft2017clinicalandgenetic pages 6-8)

11. Outcome and prognosis

Typical SPG3A has slow progression, preserved cognition, and long-term ambulation; lifespan is generally not shortened. There are no robust SPG3A-specific 5- or 10-year survival, mortality, or life-expectancy estimates. (hamamiechaar2024patientswithcomplex pages 1-2, awuah2024hereditaryspasticparaplegia pages 1-2, bick1993uncomplicated(pure)hereditary pages 1-3)

Morbidity arises from gait limitation, falls, weakness, fatigue, pain/spasms, urinary urgency, contractures, scoliosis, and eventual aid dependence. Severe biallelic or de novo presentations can include profound developmental disability, dysphagia, seizures, and wheelchair dependence. (hamamiechaar2024patientswithcomplex pages 1-2, hamamiechaar2024patientswithcomplex pages 2-4)

Likely prognostic factors include age and severity at onset, complex neurologic features, variant-specific residual function, and early development of fixed orthopedic deformity. There is no validated molecular prognostic biomarker or SPG3A risk calculator. Recovery from the genetic disorder is not expected, although function can improve with symptom treatment and rehabilitation.

12. Treatment

Present standard of care

No treatment halts or reverses ATL1 disease. Evidence is almost entirely extrapolated from mixed-HSP cohorts rather than SPG3A-specific trials. A 2019 systematic review found only 27 eligible treatment reports—17 pharmacologic, five physical-therapy, and five surgical—and concluded that the evidence base was inadequate. (bellofatto2019managementofhereditary pages 1-2)

Physical therapy and exercise: individualized stretching, strengthening, balance, aerobic conditioning, gait training, and home programs. Suggested NCIT concepts: Physical Therapy, Exercise Therapy, Rehabilitation Therapy.
Orthotics and mobility technology: ankle-foot orthoses, canes, walkers, wheelchairs, and fall-prevention adaptations. NCIT: Orthopedic Device, Assistive Device.
Oral antispasticity drugs: baclofen, tizanidine, or dantrolene, titrated to function. Weakness and sedation can worsen gait. NCIT: Pharmacologic Therapy; Muscle Relaxant Therapy. (toft2017clinicalandgenetic pages 6-8)
Focal botulinum toxin A: for function-limiting focal spasticity, combined with stretching/therapy. NCIT: Botulinum Toxin Therapy.
Intrathecal baclofen: an option for severe generalized spasticity refractory to oral therapy after a screening trial. NCIT: Intrathecal Drug Administration.
Bladder management: timed voiding, urologic assessment, and agents such as oxybutynin when appropriate. NCIT: Anticholinergic Therapy.
Orthopedic intervention: contracture or deformity procedures, including selected tendon surgery, only after multidisciplinary assessment. (maccora2024nonpharmacologicaltreatmentof pages 1-2, toft2017clinicalandgenetic pages 6-8)

Gabapentin failed to show significant improvement in the best-designed study included in the 2019 HSP review. Evidence for physical and surgical approaches was low-to-moderate quality. (bellofatto2019managementofhereditary pages 1-2)

Experimental and advanced therapeutics

GW3965/LXR activation restored lipid-droplet and cholesterol-transfer defects and rescued axonal degeneration in human SPG3A stem-cell models. Direct cholesterol exposure also rescued cellular transport and swelling phenotypes. These findings do not justify off-label human use because efficacy, dosage, blood–brain-barrier exposure, and safety are untested clinically. (mou2020impairedlipidmetabolism pages 1-2)

Gene replacement, allele-selective silencing, RNA therapy, and CRISPR correction remain conceptual/preclinical. Dominant disease may require variant-specific suppression plus replacement rather than simple gene augmentation; rare recessive loss-of-function disease could present a different therapeutic problem. No retrieved ClinicalTrials.gov record represented a disease-modifying SPG3A-specific interventional trial.

No established ATL1 pharmacogenomic rule or genotype-directed approved therapy exists.

13. Prevention

Primary lifestyle prevention is impossible because SPG3A is germline genetic disease. Vaccination, antimicrobial prophylaxis, and environmental regulation are not disease-specific measures.

Genetic primary prevention/family planning may include preconception counseling, parental testing, cascade testing, preimplantation genetic testing for a known familial pathogenic variant, chorionic-villus sampling, or amniocentesis. Counseling must address incomplete penetrance, variable expressivity, de novo disease, and rare recessive inheritance. (toft2017clinicalandgenetic pages 16-18, rudenskaya2020clinicalmolecularand pages 1-2, hamamiechaar2024patientswithcomplex pages 1-2)

Secondary prevention consists of early recognition—especially among children diagnosed with atypical cerebral palsy—and prompt rehabilitation before contractures develop. Predictive testing of asymptomatic adult relatives should follow formal genetic counseling. Testing minors is generally appropriate when surveillance or childhood intervention has potential benefit.

Tertiary prevention includes stretching, activity, orthoses, fall prevention, bladder surveillance, osteoporosis-risk management where mobility is reduced, and monitoring for scoliosis, contracture, dysphagia, and neuropathy. There is no population carrier-screening or newborn-screening program.

14. Other species and natural disease

Orthologs are conserved across mammals and major laboratory species, including Mus musculus (NCBI Taxon 10090), Rattus norvegicus (10116), Danio rerio (7955), Drosophila melanogaster (7227), and Caenorhabditis elegans (6239). Species-specific NCBI Gene IDs should be populated directly from the current NCBI Orthologs release.

No well-established naturally occurring ATL1-linked veterinary disease or breed predisposition equivalent to human SPG3A was identified. Therefore VBO breed annotations, veterinary prevalence, and cross-species transmission are unavailable/not applicable. SPG3A has no zoonotic potential.

15. Model organisms and experimental systems

Human stem-cell models

Isogenic ATL1-A161P hESCs and ATL1-P342S patient iPSCs reproduce reduced axon growth, impaired transport, swellings, astrocyte lipid-droplet defects, and defective cholesterol transfer. Genetic correction and pharmacologic rescue strengthen causal inference. Their limitations include immature cells, absence of lifelong circuitry and biomechanics, and uncertain translation of compound exposure. (mou2020impairedlipidmetabolism pages 1-2)

A 2022 microfluidic model generated autologous lower motor neurons and myotubes from three SPG3A and two SPG4 patients. HSP cultures formed fewer and less-complex NMJs and showed axonal swellings and acetylated α-tubulin accumulation. Because some outcomes were pooled across genotypes, they should not all be entered as uniquely SPG3A-specific. (costamagna2022autologousipscderivedhuman pages 1-2)

Drosophila

Atlastin knockdown/knockout causes fragmented neuronal or muscular ER, synaptic bouton abnormalities, impaired crawling/climbing, microtubule disorganization, reduced survival, and developmental defects. CRISPR knock-in variants R214C, C350R, M383T, and R192Q produced different residual-activity/severity patterns, supporting mutation-specific rather than uniform dominant-negative action. (damiani2024pluripotentstemcells pages 3-3, vivarelli2025wingsofdiscovery pages 7-8)

Zebrafish

ATL1 morphants show reduced larval motility and increased spinal-motor-axon branching. Overexpression can alter ventral development, likely through BMP-pathway effects. Zebrafish are useful for rapid developmental and compound studies but lack a mammalian corticospinal tract. (damiani2024pluripotentstemcells pages 2-3)

Rodent neuronal systems

ATL1 knockdown in mouse cortical neurons impairs axon growth and dendritic branching. Wild-type and R217Q perturbations have produced dendritic-segment or spine/protein-synthesis abnormalities in cortical or hippocampal cultures. Whole-animal SPG models often have weaker motor phenotypes than human disease, limiting natural-history and efficacy prediction. (damiani2024pluripotentstemcells pages 2-3)

Evidence limitations and knowledge-base cautions

Most treatment, quality-of-life, prognosis, and biomarker evidence is HSP-wide rather than SPG3A-specific.
Published phenotype frequencies are strongly affected by referral and family ascertainment.
Severe recessive SPG3A is supported by only a few families and should be represented as an emerging, rare inheritance mechanism—not coequal in frequency with dominant disease.
ATL1 variant mechanism is heterogeneous; do not annotate all pathogenic variants automatically as dominant-negative or complete loss-of-function.
Experimental cholesterol/LXR rescue is preclinical and must not be represented as an established treatment.
Exact HPO, GO, CL, UBERON, ORPHA, SNOMED CT, ICD-11, HGNC, NCBI Gene, and NCIT accessions should be programmatically validated against the knowledge base’s ontology release before production ingestion.

References

(rudenskaya2020clinicalmolecularand pages 1-2): G. Rudenskaya, V. Kadnikova, Christian Beetz, Tatyana N. Proskokova, I. Sermyagina, Anna A. Stepanova, Valery P. Fedotov, E. Dadaly, Darya M. Guseva, Тatiana V. Markova, and O. P. Ryzhkova. Clinical, molecular, and genetic characteristics of the hereditary spastic paraplegia type 3. №1 (2020), Mar 2020. URL: https://doi.org/10.25692/acen.2020.1.5, doi:10.25692/acen.2020.1.5. This article has 0 citations.
(hamamiechaar2024patientswithcomplex pages 1-2): Angélique Hamamie-Chaar, Mathilde Renaud, Pinar Gençpinar, Ange-Line Bruel, Christophe Philippe, Julien Maraval, Caroline Racine, Nawale Hadouiri, Laetitia Lambert, Emmanuelle Schmitt, Guillaume Banneau, Armand Hocquel, Christel Thauvin-Robinet, Laurence Faivre, and Quentin Thomas. Patients with complex and very-early-onset atl1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of spg3a. Journal of Neurology, 271:6343-6348, Jul 2024. URL: https://doi.org/10.1007/s00415-024-12565-0, doi:10.1007/s00415-024-12565-0. This article has 4 citations and is from a domain leading peer-reviewed journal.
(hamamiechaar2024patientswithcomplex pages 2-4): Angélique Hamamie-Chaar, Mathilde Renaud, Pinar Gençpinar, Ange-Line Bruel, Christophe Philippe, Julien Maraval, Caroline Racine, Nawale Hadouiri, Laetitia Lambert, Emmanuelle Schmitt, Guillaume Banneau, Armand Hocquel, Christel Thauvin-Robinet, Laurence Faivre, and Quentin Thomas. Patients with complex and very-early-onset atl1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of spg3a. Journal of Neurology, 271:6343-6348, Jul 2024. URL: https://doi.org/10.1007/s00415-024-12565-0, doi:10.1007/s00415-024-12565-0. This article has 4 citations and is from a domain leading peer-reviewed journal.
(mou2020impairedlipidmetabolism pages 1-2): Yongchao Mou, Yi Dong, Zhenyu Chen, Kyle R. Denton, Michael O. Duff, Craig Blackstone, Su-Chun Zhang, and Xue-Jun Li. Impaired lipid metabolism in astrocytes underlies degeneration of cortical projection neurons in hereditary spastic paraplegia. Acta Neuropathologica Communications, Dec 2020. URL: https://doi.org/10.1186/s40478-020-01088-0, doi:10.1186/s40478-020-01088-0. This article has 42 citations and is from a peer-reviewed journal.
(sonda2021ermorphologyin pages 5-6): Sonia Sonda, Diana Pendin, and Andrea Daga. Er morphology in the pathogenesis of hereditary spastic paraplegia. Cells, 10:2870, Oct 2021. URL: https://doi.org/10.3390/cells10112870, doi:10.3390/cells10112870. This article has 21 citations.
(crosby2021reconstitutionofhuman pages 1-2): Daniel Crosby, Melissa R. Mikolaj, Sarah B. Nyenhuis, Samantha Bryce, Jenny E. Hinshaw, and Tina H. Lee. Reconstitution of human atlastin fusion activity reveals autoinhibition by the c terminus. The Journal of Cell Biology, Nov 2021. URL: https://doi.org/10.1083/jcb.202107070, doi:10.1083/jcb.202107070. This article has 23 citations.
(maccora2024nonpharmacologicaltreatmentof pages 1-2): Simona Maccora, Angelo Torrente, Vincenzo Di Stefano, Antonino Lupica, Salvatore Iacono, Laura Pilati, Antonia Pignolo, and Filippo Brighina. Non-pharmacological treatment of hereditary spastic paraplegia: a systematic review. Neurological Sciences, 45:963-976, Nov 2024. URL: https://doi.org/10.1007/s10072-023-07200-1, doi:10.1007/s10072-023-07200-1. This article has 10 citations and is from a peer-reviewed journal.
(bellofatto2019managementofhereditary pages 1-2): Marta Bellofatto, Giovanna De Michele, Aniello Iovino, Alessandro Filla, and Filippo M. Santorelli. Management of hereditary spastic paraplegia: a systematic review of the literature. Frontiers in Neurology, Jan 2019. URL: https://doi.org/10.3389/fneur.2019.00003, doi:10.3389/fneur.2019.00003. This article has 104 citations and is from a peer-reviewed journal.
(kadnikova2019mutationalspectrumof pages 1-2): V. A. Kadnikova, G. E. Rudenskaya, A. A. Stepanova, I. G. Sermyagina, and O. P. Ryzhkova. Mutational spectrum of spast (spg4) and atl1 (spg3a) genes in russian patients with hereditary spastic paraplegia. Scientific Reports, Oct 2019. URL: https://doi.org/10.1038/s41598-019-50911-9, doi:10.1038/s41598-019-50911-9. This article has 34 citations and is from a peer-reviewed journal.
(bick1993uncomplicated(pure)hereditary pages 1-3): S Bick and GM Mirzaa. Uncomplicated (pure) hereditary spastic paraplegia overview. Unknown journal, 1993.
(costamagna2022autologousipscderivedhuman pages 1-2): Domiziana Costamagna, Valérie Casters, Marc Beltrà, Maurilio Sampaolesi, Anja Van Campenhout, Els Ortibus, Kaat Desloovere, and Robin Duelen. Autologous ipsc-derived human neuromuscular junction to model the pathophysiology of hereditary spastic paraplegia. Cells, 11:3351, Oct 2022. URL: https://doi.org/10.3390/cells11213351, doi:10.3390/cells11213351. This article has 7 citations.
(toft2017clinicalandgenetic pages 6-8): A Toft. Clinical and genetic characterization of hereditary spastic paraplegia. Unknown journal, 2017.
(denton2015modellinghereditaryspastic pages 13-17): K Denton. Modelling hereditary spastic paraplegias using human pluripotent stem cells. Unknown journal, 2015.
(OpenTargets Search: Hereditary spastic paraplegia 3A-ATL1): Open Targets Query (Hereditary spastic paraplegia 3A-ATL1, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(khan2014evidenceforautosomal pages 5-5): Tahir Naeem Khan, Joakim Klar, Muhammad Tariq, Shehla Anjum Baig, Naveed Altaf Malik, Raja Yousaf, Shahid Mahmood Baig, and Niklas Dahl. Evidence for autosomal recessive inheritance in spg3a caused by homozygosity for a novel atl1 missense mutation. European Journal of Human Genetics, 22:1180-1184, Jan 2014. URL: https://doi.org/10.1038/ejhg.2014.5, doi:10.1038/ejhg.2014.5. This article has 59 citations and is from a domain leading peer-reviewed journal.
(awuah2024hereditaryspasticparaplegia pages 1-2): Wireko Andrew Awuah, Joecelyn Kirani Tan, Anastasiia D Shkodina, Tomas Ferreira, Favour Tope Adebusoye, Adele Mazzoleni, Jack Wellington, Lian David, Ellie Chilcott, Helen Huang, Toufik Abdul-Rahman, Vallabh Shet, Oday Atallah, Jacob Kalmanovich, Riaz Jiffry, Divine Elizabeth Madhu, Kateryna Sikora, Oleksii Kmyta, and Mykhailo Yu Delva. Hereditary spastic paraplegia: novel insights into the pathogenesis and management. SAGE Open Medicine, Dec 2024. URL: https://doi.org/10.1177/20503121231221941, doi:10.1177/20503121231221941. This article has 31 citations.
(damiani2024pluripotentstemcells pages 3-3): Devid Damiani, Matteo Baggiani, Stefania Della Vecchia, Valentina Naef, and Filippo Maria Santorelli. Pluripotent stem cells as a preclinical cellular model for studying hereditary spastic paraplegias. International Journal of Molecular Sciences, 25:2615, Feb 2024. URL: https://doi.org/10.3390/ijms25052615, doi:10.3390/ijms25052615. This article has 12 citations.
(damiani2024pluripotentstemcells pages 2-3): Devid Damiani, Matteo Baggiani, Stefania Della Vecchia, Valentina Naef, and Filippo Maria Santorelli. Pluripotent stem cells as a preclinical cellular model for studying hereditary spastic paraplegias. International Journal of Molecular Sciences, 25:2615, Feb 2024. URL: https://doi.org/10.3390/ijms25052615, doi:10.3390/ijms25052615. This article has 12 citations.
(meyyazhagan2022hereditaryspasticparaplegia pages 1-2): Arun Meyyazhagan and Antonio Orlacchio. Hereditary spastic paraplegia: an update. International Journal of Molecular Sciences, 23:1697, Feb 2022. URL: https://doi.org/10.3390/ijms23031697, doi:10.3390/ijms23031697. This article has 203 citations.
(toft2017clinicalandgenetic pages 16-18): A Toft. Clinical and genetic characterization of hereditary spastic paraplegia. Unknown journal, 2017.
(vivarelli2025wingsofdiscovery pages 7-8): Rachele Vivarelli, Chiara Vantaggiato, Maria Teresa Bassi, Filippo Maria Santorelli, and Maria Marchese. Wings of discovery: using drosophila to decode hereditary spastic paraplegia and ataxias. Sep 2025. URL: https://doi.org/10.3390/cells14181466, doi:10.3390/cells14181466. This article has 1 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	9
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	46
Resolved	46
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	6
Terms named correctly	4
Terms named as a different term	1
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0008437 (4 mentions) - the report calls it "if available"; MONDO calls it hereditary spastic paraplegia 3A

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0007029 (2 mentions) - the report calls it "ER organization"; GO calls it endoplasmic reticulum organization, and lists "ER organisation" among its other names

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OpenScientist Report

Mappings

Inheritance

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Clinical Burden

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Hereditary Spastic Paraplegia 3A (SPG3A): Disease-Characteristics Report

Executive summary

1. Disease information

Definition and nomenclature

Identifiers

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

Genetic risk factors

Environmental and protective factors

3. Phenotypes

Core phenotype and suggested HPO annotations

Complex and exceptional phenotypes

Quality of life

4. Genetic and molecular information

Gene and protein

Variant spectrum and classification

Functional consequence, modifiers, epigenetics, and structural variation

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Molecular detail and recent research

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

Epidemiology

Mendelian features

10. Diagnostics

Clinical evaluation

Genetic testing strategy

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Present standard of care

Experimental and advanced therapeutics

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Human stem-cell models

Drosophila

Zebrafish

Rodent neuronal systems

Recommended resource links

Evidence limitations and knowledge-base cautions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look